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Kück U, Pöggeler S. STRIPAK, a fundamental signaling hub of eukaryotic development. Microbiol Mol Biol Rev 2024; 88:e0020523. [PMID: 39526753 DOI: 10.1128/mmbr.00205-23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2024] Open
Abstract
SUMMARYThe striatin-interacting phosphatase and kinase (STRIPAK) complex is involved in the regulation of many developmental processes in eukaryotic microorganisms and all animals, including humans. STRIPAK is a component of protein phosphatase 2A (PP2A), a highly conserved serine-threonine phosphatase composed of catalytic subunits (PP2Ac), a scaffolding subunit (PP2AA) and various substrate-directing B regulatory subunits. In particular, the B''' regulatory subunit called striatin has evoked major interest over the last 20 years. Studies in fungal systems have contributed substantially to our current knowledge about STRIPAK composition, assembly, and cellular localization, as well as its regulatory role in autophagy and the morphology of fungal development. STRIPAK represents a signaling hub with many kinases and thus integrates upstream and downstream information from many conserved eukaryotic signaling pathways. A profound understanding of STRIPAK's regulatory role in fungi opens the gateway to understanding the multifarious functions carried out by STRIPAK in higher eukaryotes, including its contribution to malignant cell growth.
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Affiliation(s)
- Ulrich Kück
- Allgemeine & Molekulare Botanik, Ruhr-University, Bochum, Germany
| | - Stefanie Pöggeler
- Department of Genetics of Eukaryotic Microorganisms, Institute of Microbiology and Genetics, Georg-August-University, Göttingen, Germany
- Göttingen Center for Molecular Biosciences (GZMB), Georg-August-University, Göttingen, Germany
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Abedimanesh S, Safaralizadeh R, Jahanafrooz Z, Najafi S, Amini M, Nazarloo SS, Bahojb Mahdavi SZ, Baradaran B, Jebelli A, Mokhtarzadeh AA. Interaction of noncoding RNAs with hippo signaling pathway in cancer cells and cancer stem cells. Noncoding RNA Res 2024; 9:1292-1307. [PMID: 39045083 PMCID: PMC11263728 DOI: 10.1016/j.ncrna.2024.06.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2024] [Revised: 06/02/2024] [Accepted: 06/05/2024] [Indexed: 07/25/2024] Open
Abstract
The Hippo signaling pathway has a regulatory function in the organogenesis process and cellular homeostasis, switching the cascade reactions of crucial kinases acts to turn off/on the Hippo pathway, altering the downstream gene expression and thereby regulating proliferation, apoptosis, or stemness. Disruption of this pathway can lead to the occurrence of various disorders and different types of cancer. Recent findings highlight the importance of ncRNAs, such as microRNA, circular RNA, and lncRNAs, in modulating the Hippo pathway. Defects in ncRNAs can disrupt Hippo pathway balance, increasing tumor cells, tumorigenesis, and chemotherapeutic resistance. This review summarizes ncRNAs' inhibitory or stimulatory role in - Hippo pathway regulation in cancer and stem cells. Identifying the relation between ncRNAs and the components of this pathway could pave the way for developing new biomarkers in the treatment and diagnosis of cancers.
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Affiliation(s)
- Saba Abedimanesh
- Department of Animal Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran
| | - Reza Safaralizadeh
- Department of Animal Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran
| | - Zohreh Jahanafrooz
- Department of Biology, Faculty of Sciences, University of Maragheh, Maragheh, Iran
| | - Souzan Najafi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Amini
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Shabnam Soltani Nazarloo
- Department of Biology, Faculty of Basic Sciences, Azarbaijan Shahid Madani University, Tabriz, Iran
| | | | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Asiyeh Jebelli
- Department of Biological Sciences, Faculty of Basic Sciences, Higher Education Institute of Rab-Rashid, Tabriz, Iran
- Clinical Research Development Unit of Tabriz Valiasr Hospital, Tabriz University of Medical Sciences, Tabriz, Iran
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Monteagudo-Sánchez A, Richard Albert J, Scarpa M, Noordermeer D, Greenberg MC. The impact of the embryonic DNA methylation program on CTCF-mediated genome regulation. Nucleic Acids Res 2024; 52:10934-10950. [PMID: 39180406 PMCID: PMC11472158 DOI: 10.1093/nar/gkae724] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2023] [Revised: 07/23/2024] [Accepted: 08/21/2024] [Indexed: 08/26/2024] Open
Abstract
During mammalian embryogenesis, both the 5-cytosine DNA methylation (5meC) landscape and three dimensional (3D) chromatin architecture are profoundly remodeled during a process known as 'epigenetic reprogramming.' An understudied aspect of epigenetic reprogramming is how the 5meC flux, per se, affects the 3D genome. This is pertinent given the 5meC-sensitivity of DNA binding for a key regulator of chromosome folding: CTCF. We profiled the CTCF binding landscape using a mouse embryonic stem cell (ESC) differentiation protocol that models embryonic 5meC dynamics. Mouse ESCs lacking DNA methylation machinery are able to exit naive pluripotency, thus allowing for dissection of subtle effects of CTCF on gene expression. We performed CTCF HiChIP in both wild-type and mutant conditions to assess gained CTCF-CTCF contacts in the absence of 5meC. We performed H3K27ac HiChIP to determine the impact that ectopic CTCF binding has on cis-regulatory contacts. Using 5meC epigenome editing, we demonstrated that the methyl-mark is able to impair CTCF binding at select loci. Finally, a detailed dissection of the imprinted Zdbf2 locus showed how 5meC-antagonism of CTCF allows for proper gene regulation during differentiation. This work provides a comprehensive overview of how 5meC impacts the 3D genome in a relevant model for early embryonic events.
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Affiliation(s)
| | | | - Margherita Scarpa
- Université Paris Cité, CNRS, Institut Jacques Monod, F-75013 Paris, France
| | - Daan Noordermeer
- Université Paris-Saclay, CEA, CNRS, Institute for Integrative Biology of the Cell (I2BC), F-91998 Gif-sur-Yvette, France
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Sun J, Zhang JX, Li MS, Qin MB, Cheng RX, Wu QR, Chen QL, Yang D, Liao C, Liu SQ, Huang JA. Loss of monopolar spindle-binding protein 3B expression promotes colorectal cancer invasiveness by activation of target of rapamycin kinase/autophagy signaling. World J Gastroenterol 2024; 30:3229-3246. [PMID: 39086630 PMCID: PMC11287403 DOI: 10.3748/wjg.v30.i26.3229] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Revised: 05/28/2024] [Accepted: 06/03/2024] [Indexed: 07/09/2024] Open
Abstract
BACKGROUND Monopolar spindle-binding protein 3B (MOB3B) functions as a signal transducer and altered MOB3B expression is associated with the development of human cancers. AIM To investigate the role of MOB3B in colorectal cancer (CRC). METHODS This study collected 102 CRC tissue samples for immunohistochemical detection of MOB3B expression for association with CRC prognosis. After overexpression and knockdown of MOB3B expression were induced in CRC cell lines, changes in cell viability, migration, invasion, and gene expression were assayed. Tumor cell autophagy was detected using transmission electron microscopy, while nude mouse xenograft experiments were performed to confirm the in-vitro results. RESULTS MOB3B expression was reduced in CRC vs normal tissues and loss of MOB3B expression was associated with poor CRC prognosis. Overexpression of MOB3B protein in vitro attenuated the cell viability as well as the migration and invasion capacities of CRC cells, whereas knockdown of MOB3B expression had the opposite effects in CRC cells. At the molecular level, microtubule-associated protein light chain 3 II/I expression was elevated, whereas the expression of matrix metalloproteinase (MMP)2, MMP9, sequestosome 1, and phosphorylated mechanistic target of rapamycin kinase (mTOR) was downregulated in MOB3B-overexpressing RKO cells. In contrast, the opposite results were observed in tumor cells with MOB3B knockdown. The nude mouse data confirmed these in-vitro findings, i.e., MOB3B expression suppressed CRC cell xenograft growth, whereas knockdown of MOB3B expression promoted the growth of CRC cell xenografts. CONCLUSION Loss of MOB3B expression promotes CRC development and malignant behaviors, suggesting a potential tumor suppressive role of MOB3B in CRC by inhibition of mTOR/autophagy signaling.
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Affiliation(s)
- Juan Sun
- Department of Gastroenterology, The Second Affiliated Hospital of Guangxi Medical University, Nanning 530007, Guangxi Zhuang Autonomous Region, China
| | - Jin-Xiu Zhang
- Department of Gastroenterology, The Second Affiliated Hospital of Guangxi Medical University, Nanning 530007, Guangxi Zhuang Autonomous Region, China
| | - Meng-Shi Li
- Department of Gastroenterology, The Second Affiliated Hospital of Guangxi Medical University, Nanning 530007, Guangxi Zhuang Autonomous Region, China
| | - Meng-Bin Qin
- Department of Gastroenterology, The Second Affiliated Hospital of Guangxi Medical University, Nanning 530007, Guangxi Zhuang Autonomous Region, China
| | - Ruo-Xi Cheng
- Department of Gastroenterology, The Second Affiliated Hospital of Guangxi Medical University, Nanning 530007, Guangxi Zhuang Autonomous Region, China
| | - Qing-Ru Wu
- Department of Gastroenterology, The Second Affiliated Hospital of Guangxi Medical University, Nanning 530007, Guangxi Zhuang Autonomous Region, China
| | - Qiu-Ling Chen
- Department of Gastroenterology, The Second Affiliated Hospital of Guangxi Medical University, Nanning 530007, Guangxi Zhuang Autonomous Region, China
| | - Dan Yang
- Department of Gastroenterology, The Second Affiliated Hospital of Guangxi Medical University, Nanning 530007, Guangxi Zhuang Autonomous Region, China
| | - Cun Liao
- Department of Colorectal & Anal Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Shi-Quan Liu
- Department of Gastroenterology, The Second Affiliated Hospital of Guangxi Medical University, Nanning 530007, Guangxi Zhuang Autonomous Region, China
| | - Jie-An Huang
- Department of Gastroenterology, The Second Affiliated Hospital of Guangxi Medical University, Nanning 530007, Guangxi Zhuang Autonomous Region, China
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Sridhara S. Multiple structural flavors of RNase P in precursor tRNA processing. WILEY INTERDISCIPLINARY REVIEWS. RNA 2024; 15:e1835. [PMID: 38479802 DOI: 10.1002/wrna.1835] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/28/2023] [Revised: 01/26/2024] [Accepted: 01/29/2024] [Indexed: 06/06/2024]
Abstract
The precursor transfer RNAs (pre-tRNAs) require extensive processing to generate mature tRNAs possessing proper fold, structural stability, and functionality required to sustain cellular viability. The road to tRNA maturation follows an ordered process: 5'-processing, 3'-processing, modifications at specific sites, if any, and 3'-CCA addition before aminoacylation and recruitment to the cellular protein synthesis machinery. Ribonuclease P (RNase P) is a universally conserved endonuclease in all domains of life, performing the hydrolysis of pre-tRNA sequences at the 5' end by the removal of phosphodiester linkages between nucleotides at position -1 and +1. Except for an archaeal species: Nanoarchaeum equitans where tRNAs are transcribed from leaderless-position +1, RNase P is indispensable for life and displays fundamental variations in terms of enzyme subunit composition, mechanism of substrate recognition and active site architecture, utilizing in all cases a two metal ion-mediated conserved catalytic reaction. While the canonical RNA-based ribonucleoprotein RNase P has been well-known to occur in bacteria, archaea, and eukaryotes, the occurrence of RNA-free protein-only RNase P in eukaryotes and RNA-free homologs of Aquifex RNase P in prokaryotes has been discovered more recently. This review aims to provide a comprehensive overview of structural diversity displayed by various RNA-based and RNA-free RNase P holoenzymes towards harnessing critical RNA-protein and protein-protein interactions in achieving conserved pre-tRNA processing functionality. Furthermore, alternate roles and functional interchangeability of RNase P are discussed in the context of its employability in several clinical and biotechnological applications. This article is categorized under: RNA Processing > tRNA Processing RNA Evolution and Genomics > RNA and Ribonucleoprotein Evolution RNA Interactions with Proteins and Other Molecules > RNA-Protein Complexes.
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Affiliation(s)
- Sagar Sridhara
- Department of Medical Biochemistry and Cell Biology, University of Gothenburg, Gothenburg, Sweden
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Lu J, Feng Y, Yu D, Li H, Li W, Chen H, Chen L. A review of nuclear Dbf2-related kinase 1 (NDR1) protein interaction as promising new target for cancer therapy. Int J Biol Macromol 2024; 259:129188. [PMID: 38184050 DOI: 10.1016/j.ijbiomac.2023.129188] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2023] [Revised: 12/19/2023] [Accepted: 12/31/2023] [Indexed: 01/08/2024]
Abstract
Nuclear Dbf2-related kinase 1 (NDR1) is a nuclear Dbf2-related (NDR) protein kinase family member, which regulates cell functions and participates in cell proliferation and differentiation through kinase activity. NDR1 regulates physiological functions by interacting with different proteins. Protein-protein interactions (PPIs) are crucial for regulating biological processes and controlling cell fate, and as a result, it is beneficial to study the actions of PPIs to elucidate the pathological mechanism of diseases. The previous studies also show that the expression of NDR1 is deregulated in numerous human cancer samples and it needs the context-specific targeting strategies for NDR1. Thus, a comprehensive understanding of the direct interaction between NDR1 and varieties of proteins may provide new insights into cancer therapies. In this review, we summarize recent studies of NDR1 in solid tumors, such as prostate cancer and breast cancer, and explore the mechanism of action of PPIs of NDR1 in tumors.
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Affiliation(s)
- Jiani Lu
- Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Yanjun Feng
- Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China
| | - Danmei Yu
- Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Hongtao Li
- Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Weihua Li
- Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China
| | - Hongzhuan Chen
- Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Lili Chen
- Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
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Li AX, Martin TA, Lane J, Jiang WG. Cellular Impacts of Striatins and the STRIPAK Complex and Their Roles in the Development and Metastasis in Clinical Cancers (Review). Cancers (Basel) 2023; 16:76. [PMID: 38201504 PMCID: PMC10777921 DOI: 10.3390/cancers16010076] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2023] [Revised: 12/18/2023] [Accepted: 12/20/2023] [Indexed: 01/12/2024] Open
Abstract
Striatins (STRNs) are generally considered to be cytoplasmic proteins, with lower expression observed in the nucleus and at cell-cell contact regions. Together with protein phosphatase 2A (PP2A), STRNs form the core region of striatin-interacting phosphatase and kinase (STRIPAK) complexes through the coiled-coil region of STRN proteins, which is crucial for substrate recruitment. Over the past two decades, there has been an increasing amount of research into the biological and cellular functions of STRIPAK members. STRNs and the constituent members of the STRIPAK complex have been found to regulate several cellular functions, such as cell cycle control, cell growth, and motility. Dysregulation of these cellular events is associated with cancer development. Importantly, their roles in cancer cells and clinical cancers are becoming recognised, with several STRIPAK components found to have elevated expression in cancerous tissues compared to healthy tissues. These molecules exhibit significant diagnostic and prognostic value across different cancer types and in metastatic progression. The present review comprehensively summarises and discusses the current knowledge of STRNs and core STRIPAK members, in cancer malignancy, from both cellular and clinical perspectives.
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Affiliation(s)
| | - Tracey A. Martin
- Cardiff China Medical Research Collaborative, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK; (A.X.L.); (J.L.); (W.G.J.)
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Maharati A, Tolue Ghasaban F, Akhlaghipour I, Taghehchian N, Zangouei AS, Moghbeli M. MicroRNA-495: a therapeutic and diagnostic tumor marker. J Mol Histol 2023; 54:559-578. [PMID: 37759132 DOI: 10.1007/s10735-023-10159-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Accepted: 09/18/2023] [Indexed: 09/29/2023]
Abstract
Therapeutic and diagnostic progresses have significantly reduced the mortality rate among cancer patients during the last decade. However, there is still a high rate of mortality among cancer patients. One of the important reasons involved in the high mortality rate is the late diagnosis in advanced tumor stages that causes the failure of therapeutic strategies in these patients. Therefore, investigating the molecular mechanisms involved in tumor progression has an important role in introducing the efficient early detection markers. MicroRNAs (miRNAs) as stable factors in body fluids are always considered as non-invasive diagnostic and prognostic markers. In the present review, we investigated the role of miR-495 in tumor progression. It has been reported that miR-495 has mainly a tumor suppressor function through the regulation of transcription factors and tyrosine kinases as well as cellular processes such as multidrug resistance, chromatin remodeling, and signaling pathways. This review can be an effective step towards introducing the miR-495 as a non-invasive diagnostic/prognostic marker as well as a suitable target in tumor therapy.
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Affiliation(s)
- Amirhosein Maharati
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Faezeh Tolue Ghasaban
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Iman Akhlaghipour
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Negin Taghehchian
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amir Sadra Zangouei
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Meysam Moghbeli
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
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Bisoyi P, Ratna D, Kumar G, Mallick BN, Goswami SK. In the Rat Midbrain, SG2NA and DJ-1 have Common Interactome, Including Mitochondrial Electron Transporters that are Comodulated Under Oxidative Stress. Cell Mol Neurobiol 2023; 43:3061-3080. [PMID: 37165139 PMCID: PMC11410017 DOI: 10.1007/s10571-023-01356-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Accepted: 04/26/2023] [Indexed: 05/12/2023]
Abstract
Scaffold proteins Striatin and SG2NA assemble kinases and phosphatases into the signalling complexes called STRIPAK. Dysfunctional STRIPAKs cause cancer, cerebral cavernous malformations, etc. DJ-1, a sensor for oxidative stress, has long been associated with the Parkinson's disease, cancer, and immune disorders. SG2NA interacts with DJ-1 and Akt providing neuroprotection under oxidative stress. To dissect the role of SG2NA and DJ-1 in neuronal pathobiology, rat midbrain extracts were immunoprecipitated with SG2NA and sixty-three interacting proteins were identified. BN-PAGE followed by the LC-MS/MS showed 1030 comigrating proteins as the potential constituents of the multimeric complexes formed by SG2NA. Forty-three proteins were common between those identified by co-immunoprecipitation and the BN-PAGE. Co-immunoprecipitation with DJ-1 identified 179 interacting partners, of which forty-one also interact with SG2NA. Among those forty-one proteins immunoprecipitated with both SG2NA and DJ-1, thirty-nine comigrated with SG2NA in the BN-PAGE, and thus are bonafide constituents of the supramolecular assemblies comprising both DJ-1 and SG2NA. Among those thirty-nine proteins, seven are involved in mitochondrial oxidative phosphorylation. In rotenone-treated rats having Parkinson's like symptoms, the levels of both SG2NA and DJ-1 increased in the mitochondria; and the association of SG2NA with the electron transport complexes enhanced. In the hemi-Parkinson's model, where the rats were injected with 6-OHDA into the midbrain, the occupancy of SG2NA and DJ-1 in the mitochondrial complexes also increased. Our study thus reveals a new family of potential STRIPAK assemblies involving both SG2NA and DJ-1, with key roles in protecting midbrain from the oxidative stress.
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Affiliation(s)
- Padmini Bisoyi
- School of Life Sciences, Jawaharlal Nehru University, New Mehrauli Road, New Delhi, 110067, India
| | - Deshdeepak Ratna
- School of Life Sciences, Jawaharlal Nehru University, New Mehrauli Road, New Delhi, 110067, India
| | - Gaurav Kumar
- Department of Life Sciences and Biotechnology, CSJM University, Kanpur, Uttar Pradesh, 208024, India
| | - Birendra Nath Mallick
- School of Life Sciences, Jawaharlal Nehru University, New Mehrauli Road, New Delhi, 110067, India
- Amity Institute of Neuropsychology & Neurosciences, Amity University, Noida, 201313, India
| | - Shyamal K Goswami
- School of Life Sciences, Jawaharlal Nehru University, New Mehrauli Road, New Delhi, 110067, India.
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Elkholi IE, Boulais J, Thibault MP, Phan HD, Robert A, Lai LB, Faubert D, Smith MJ, Gopalan V, Côté JF. Mapping the MOB proteins' proximity network reveals a unique interaction between human MOB3C and the RNase P complex. J Biol Chem 2023; 299:105123. [PMID: 37536630 PMCID: PMC10480535 DOI: 10.1016/j.jbc.2023.105123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Revised: 07/20/2023] [Accepted: 07/23/2023] [Indexed: 08/05/2023] Open
Abstract
Distinct functions mediated by members of the monopolar spindle-one-binder (MOB) family of proteins remain elusive beyond the evolutionarily conserved and well-established roles of MOB1 (MOB1A/B) in regulating tissue homeostasis within the Hippo pathway. Since MOB proteins are adaptors, understanding how they engage in protein-protein interactions and help assemble complexes is essential to define the full scope of their biological functions. To address this, we undertook a proximity-dependent biotin identification approach to define the interactomes of all seven human MOB proteins in HeLa and human embryonic kidney 293 cell lines. We uncovered >200 interactions, of which at least 70% are unreported on BioGrid. The generated dataset reliably recalled the bona fide interactors of the well-studied MOBs. We further defined the common and differential interactome between different MOBs on a subfamily and an individual level. We discovered a unique association between MOB3C and 7 of 10 protein subunits of the RNase P complex, an endonuclease that catalyzes tRNA 5' maturation. As a proof of principle for the robustness of the generated dataset, we validated the specific interaction of MOB3C with catalytically active RNase P by using affinity purification-mass spectrometry and pre-tRNA cleavage assays of MOB3C pulldowns. In summary, our data provide novel insights into the biology of MOB proteins and reveal the first interactors of MOB3C, components of the RNase P complex, and hence an exciting nexus with RNA biology.
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Affiliation(s)
- Islam E Elkholi
- Montreal Clinical Research Institute (IRCM), Montreal, Quebec, Canada; Molecular Biology Programs, Université de Montréal, Montreal, Quebec, Canada; Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec, Canada.
| | - Jonathan Boulais
- Montreal Clinical Research Institute (IRCM), Montreal, Quebec, Canada
| | | | - Hong-Duc Phan
- Department of Chemistry & Biochemistry, Center for RNA Biology, The Ohio State University, Columbus, Ohio, USA
| | - Amélie Robert
- Montreal Clinical Research Institute (IRCM), Montreal, Quebec, Canada
| | - Lien B Lai
- Department of Chemistry & Biochemistry, Center for RNA Biology, The Ohio State University, Columbus, Ohio, USA
| | - Denis Faubert
- Montreal Clinical Research Institute (IRCM), Montreal, Quebec, Canada
| | - Matthew J Smith
- Institute for Research in Immunology and Cancer, Université de Montréal, Montreal, Quebec, Canada
| | - Venkat Gopalan
- Department of Chemistry & Biochemistry, Center for RNA Biology, The Ohio State University, Columbus, Ohio, USA
| | - Jean-Franҫois Côté
- Montreal Clinical Research Institute (IRCM), Montreal, Quebec, Canada; Molecular Biology Programs, Université de Montréal, Montreal, Quebec, Canada; Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec, Canada; Department of Biochemistry and Molecular Medicine, Université de Montréal, Montreal, Quebec, Canada.
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11
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Hudson J, Paul S, Veraksa A, Ghabrial A, Harvey KF, Poon C. NDR kinase tricornered genetically interacts with Ccm3 and metabolic enzymes in Drosophila melanogaster tracheal development. G3 (BETHESDA, MD.) 2023; 13:6991444. [PMID: 36653023 PMCID: PMC9997570 DOI: 10.1093/g3journal/jkad013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Revised: 07/18/2022] [Accepted: 12/14/2022] [Indexed: 01/20/2023]
Abstract
The Germinal Center Kinase III (GckIII) pathway is a Hippo-like kinase module defined by sequential activation of Ste20 kinases Thousand and One (Tao) and GckIII, followed by nuclear dbf2-related (NDR) kinase Tricornered (Trc). We previously uncovered a role for the GckIII pathway in Drosophila melanogaster tracheal (respiratory) tube morphology. The trachea form a network of branched epithelial tubes essential for oxygen transport, and are structurally analogous to branched tubular organs in vertebrates, such as the vascular system. In the absence of GckIII pathway function, aberrant dilations form in tracheal tubes characterized by mislocalized junctional and apical proteins, suggesting that the pathway is important in maintaining tube integrity in development. Here, we observed a genetic interaction between trc and Cerebral cavernous malformations 3 (Ccm3), the Drosophila ortholog of a human vascular disease gene, supporting our hypothesis that the GckIII pathway functions downstream of Ccm3 in trachea, and potentially in the vertebrate cerebral vasculature. However, how GckIII pathway signaling is regulated and the mechanisms that underpin its function in tracheal development are unknown. We undertook biochemical and genetic approaches to identify proteins that interact with Trc, the most downstream GckIII pathway kinase. We found that known GckIII and NDR scaffold proteins are likely to control GckIII pathway signaling in tracheal development, consistent with their conserved roles in Hippo-like modules. Furthermore, we show genetic interactions between trc and multiple enzymes in glycolysis and oxidative phosphorylation, suggesting a potential function of the GckIII pathway in integrating cellular energy requirements with maintenance of tube integrity.
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Affiliation(s)
- Joshua Hudson
- Peter MacCallum Cancer Centre, 305 Grattan Street, Melbourne, Victoria 3000, Australia.,Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria 3010, Australia
| | - Sayantanee Paul
- Department of Biology, University of Massachusetts Boston, Boston, MA 02125, USA
| | - Alexey Veraksa
- Department of Biology, University of Massachusetts Boston, Boston, MA 02125, USA
| | - Amin Ghabrial
- Department of Pathology and Cell Biology, Columbia University College of Physicians and Surgeons, 630 West 168th Street, New York, NY 10032, USA
| | - Kieran F Harvey
- Peter MacCallum Cancer Centre, 305 Grattan Street, Melbourne, Victoria 3000, Australia.,Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria 3010, Australia.,Department of Anatomy and Developmental Biology, and Biomedicine Discovery Institute, Monash University, Clayton 3800, Australia
| | - Carole Poon
- Peter MacCallum Cancer Centre, 305 Grattan Street, Melbourne, Victoria 3000, Australia.,Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria 3010, Australia
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12
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Zhang Z, Freeman M, Zhang Y, El-Nachef D, Davenport G, Williams A, MacLellan WR. Hippo signaling and histone methylation control cardiomyocyte cell cycle re-entry through distinct transcriptional pathways. PLoS One 2023; 18:e0281610. [PMID: 36780463 PMCID: PMC9925018 DOI: 10.1371/journal.pone.0281610] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Accepted: 01/26/2023] [Indexed: 02/15/2023] Open
Abstract
AIMS Accumulating data demonstrates that new adult cardiomyocytes (CMs) are generated throughout life from pre-existing CMs, although the absolute magnitude of CM self-renewal is very low. Modifying epigenetic histone modifications or activating the Hippo-Yap pathway have been shown to promote adult CM cycling and proliferation. Whether these interventions work through common pathways or act independently is unknown. For the first time we have determined whether lysine demethylase 4D (KDM4D)-mediated CM-specific H3K9 demethylation and Hippo pathways inhibition have additive or redundant roles in promoting CM cell cycle re-entry. METHODS AND RESULTS We found that activating Yap1 in cultured neonatal rat ventricular myocytes (NRVM) through overexpressing Hippo pathway inhibitor, miR-199, preferentially increased S-phase CMs, while H3K9me3 demethylase KDM4D preferentially increased G2/M markers in CMs. Together KDM4D and miR-199 further increased total cell number of NRVMs in culture. Inhibition of Hippo signaling via knock-down of Salvador Family WW Domain Containing Protein 1 (Sav1) also led to S-phase reactivation and additional cell cycle re-entry was seen when combined with KDM4D overexpression. Inducible activating KDM4D (iKDM4D) in adult transgenic mice together with shRNA mediated knock-down of Sav1 (iKDM4D+Sav1-sh) resulted in a significant increase in cycling CMs compared to either intervention alone. KDM4D preferentially induced expression of genes regulating late (G2/M) phases of the cell cycle, while miR-199 and si-Sav1 preferentially up-regulated genes involved in G1/S phase. KDM4D upregulated E2F1 and FoxM1 expression, whereas miR-199 and si-Sav1 induced Myc. Using transgenic mice over-expressing KDM4D together with Myc, we demonstrated that KDM4D/Myc significantly increased CM cell cycling but did not affect cardiac function. CONCLUSIONS KDM4D effects on CM cell cycle activity are additive with the Hippo-Yap1 pathway and appear to preferentially regulate different cell cycle regulators. This may have important implications for strategies that target cardiac regeneration in treating heart disease.
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Affiliation(s)
- Zhenhe Zhang
- Cardiology Division, Department of Medicine, University of Washington, Seattle, Washington, United States of America
- Center for Cardiovascular Biology, University of Washington, Seattle, Washington, United States of America
- Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington, United States of America
| | - Miles Freeman
- Cardiology Division, Department of Medicine, University of Washington, Seattle, Washington, United States of America
- Center for Cardiovascular Biology, University of Washington, Seattle, Washington, United States of America
- Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington, United States of America
| | - Yiqiang Zhang
- Cardiology Division, Department of Medicine, University of Washington, Seattle, Washington, United States of America
- Center for Cardiovascular Biology, University of Washington, Seattle, Washington, United States of America
- Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington, United States of America
- Department of Anatomy, Biochemistry and Physiology, John A. Burn School of Medicine, University of Hawaii, Honolulu, Hawaii, United States of America
| | - Danny El-Nachef
- Cardiology Division, Department of Medicine, University of Washington, Seattle, Washington, United States of America
- Center for Cardiovascular Biology, University of Washington, Seattle, Washington, United States of America
- Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington, United States of America
| | - George Davenport
- Cardiology Division, Department of Medicine, University of Washington, Seattle, Washington, United States of America
- Center for Cardiovascular Biology, University of Washington, Seattle, Washington, United States of America
- Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington, United States of America
| | - Allison Williams
- Cardiology Division, Department of Medicine, University of Washington, Seattle, Washington, United States of America
- Center for Cardiovascular Biology, University of Washington, Seattle, Washington, United States of America
- Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington, United States of America
| | - W. Robb MacLellan
- Cardiology Division, Department of Medicine, University of Washington, Seattle, Washington, United States of America
- Center for Cardiovascular Biology, University of Washington, Seattle, Washington, United States of America
- Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington, United States of America
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13
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Construction and functional enrichment analysis of the competitive endogenous RNA regulatory network for nonarteritic anterior ischemic optic neuropathy based on high-throughput sequencing. Funct Integr Genomics 2022; 22:1253-1267. [DOI: 10.1007/s10142-022-00914-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Revised: 09/26/2022] [Accepted: 11/03/2022] [Indexed: 11/11/2022]
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14
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mRNA Capture Sequencing and RT-qPCR for the Detection of Pathognomonic, Novel, and Secondary Fusion Transcripts in FFPE Tissue: A Sarcoma Showcase. Int J Mol Sci 2022; 23:ijms231911007. [PMID: 36232302 PMCID: PMC9569610 DOI: 10.3390/ijms231911007] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Revised: 09/12/2022] [Accepted: 09/12/2022] [Indexed: 11/17/2022] Open
Abstract
We assess the performance of mRNA capture sequencing to identify fusion transcripts in FFPE tissue of different sarcoma types, followed by RT-qPCR confirmation. To validate our workflow, six positive control tumors with a specific chromosomal rearrangement were analyzed using the TruSight RNA Pan-Cancer Panel. Fusion transcript calling by FusionCatcher confirmed these aberrations and enabled the identification of both fusion gene partners and breakpoints. Next, whole-transcriptome TruSeq RNA Exome sequencing was applied to 17 fusion gene-negative alveolar rhabdomyosarcoma (ARMS) or undifferentiated round cell sarcoma (URCS) tumors, for whom fluorescence in situ hybridization (FISH) did not identify the classical pathognomonic rearrangements. For six patients, a pathognomonic fusion transcript was readily detected, i.e., PAX3-FOXO1 in two ARMS patients, and EWSR1-FLI1, EWSR1-ERG, or EWSR1-NFATC2 in four URCS patients. For the 11 remaining patients, 11 newly identified fusion transcripts were confirmed by RT-qPCR, including COPS3-TOM1L2, NCOA1-DTNB, WWTR1-LINC01986, PLAA-MOB3B, AP1B1-CHEK2, and BRD4-LEUTX fusion transcripts in ARMS patients. Additionally, recurrently detected secondary fusion transcripts in patients diagnosed with EWSR1-NFATC2-positive sarcoma were confirmed (COPS4-TBC1D9, PICALM-SYTL2, SMG6-VPS53, and UBE2F-ALS2). In conclusion, this study shows that mRNA capture sequencing enhances the detection rate of pathognomonic fusions and enables the identification of novel and secondary fusion transcripts in sarcomas.
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15
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Han KJ, Mikalayeva V, Gerber SA, Kettenbach AN, Skeberdis VA, Prekeris R. Rab40c regulates focal adhesions and PP6 activity by controlling ANKRD28 ubiquitylation. Life Sci Alliance 2022; 5:5/9/e202101346. [PMID: 35512830 PMCID: PMC9070665 DOI: 10.26508/lsa.202101346] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Revised: 04/26/2022] [Accepted: 04/26/2022] [Indexed: 11/24/2022] Open
Abstract
Rab40c is a SOCS box-containing protein which binds Cullin5 to form a ubiquitin E3 ligase complex (Rab40c/CRL5) to regulate protein ubiquitylation. However, the exact functions of Rab40c remain to be determined, and what proteins are the targets of Rab40c-Cullin5-mediated ubiquitylation in mammalian cells are unknown. Here we showed that in migrating MDA-MB-231 cells Rab40c regulates focal adhesion's number, size, and distribution. Mechanistically, we found that Rab40c binds the protein phosphatase 6 (PP6) complex and ubiquitylates one of its subunits, ankyrin repeat domain 28 (ANKRD28), thus leading to its lysosomal degradation. Furthermore, we identified that phosphorylation of FAK and MOB1 is decreased in Rab40c knock-out cells, which may contribute to focal adhesion site regulation by Rab40c. Thus, we propose a model where Rab40c/CRL5 regulates ANKRD28 ubiquitylation and degradation, leading to a decrease in PP6 activity, which ultimately affects FAK and Hippo pathway signaling to alter focal adhesion dynamics.
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Affiliation(s)
- Ke-Jun Han
- Department of Cell and Developmental Biology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Valeryia Mikalayeva
- Institute of Cardiology, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Scott A Gerber
- Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Hanover, NH, USA.,Norris Cotton Cancer Center, Lebanon, NH, USA
| | - Arminja N Kettenbach
- Department of Biochemistry and Cell Biology, Geisel School of Medicine at Dartmouth, Hanover, NH, USA.,Norris Cotton Cancer Center, Lebanon, NH, USA
| | - Vytenis A Skeberdis
- Institute of Cardiology, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Rytis Prekeris
- Department of Cell and Developmental Biology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
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16
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Yousefi H, Delavar MR, Piroozian F, Baghi M, Nguyen K, Cheng T, Vittori C, Worthylake D, Alahari SK. Hippo signaling pathway: A comprehensive gene expression profile analysis in breast cancer. Biomed Pharmacother 2022; 151:113144. [PMID: 35623167 DOI: 10.1016/j.biopha.2022.113144] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Revised: 05/10/2022] [Accepted: 05/15/2022] [Indexed: 11/30/2022] Open
Abstract
Breast cancer (BC) is the most frequently diagnosed malignancy in women and a major public health concern. The Hippo pathway is an evolutionarily conserved signaling pathway that serves as a key regulator for a wide variety of biological processes. Hippo signaling has been shown to have both oncogenic and tumor-suppressive functions in various cancers. Core components of the Hippo pathway consist of various kinases and downstream effectors such as YAP/TAZ. In the current report, differential expression of Hippo pathway elements as well as the correlation of Hippo pathway mRNAs with various clinicopathologic characteristics, including molecular subtypes, receptor status, and methylation status, has been investigated in BC using METABRIC and TCGA datasets. In this review, we note deregulation of several Hippo signaling elements in BC patients. Moreover, we see examples of negative correlations between methylation of Hippo genes and mRNA expression. The expression of Hippo genes significantly varies between different receptor subgroups. Because of the clear associations between mRNA expression and methylation status, DNA methylation may be one of the mechanisms that regulate the Hippo pathway in BC cells. Differential expression of Hippo genes among various BC molecular subtypes suggests that Hippo signaling may function differently in different subtypes of BC. Our data also highlights an interesting link between Hippo components' transcription and ER negativity in BC. In conclusion, substantial deregulation of Hippo signaling components suggests an important role of these genes in breast cancer.
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Affiliation(s)
- Hassan Yousefi
- Louisiana State University Health Science Center (LSUHSC), Biochemistry & Molecular Biology, New Orleans, LA, USA
| | - Mahsa Rostamian Delavar
- Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran
| | | | - Masoud Baghi
- Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran
| | - Khoa Nguyen
- Department of Medicine, Tulane University School of Medicine, New Orleans, LA, USA
| | - Thomas Cheng
- Department of Medicine, Tulane University School of Medicine, New Orleans, LA, USA
| | - Cecilia Vittori
- Louisiana State University Health Sciences Center and Stanley S. Scott Cancer Center, New Orleans, LA, USA
| | - David Worthylake
- Louisiana State University Health Science Center (LSUHSC), Biochemistry & Molecular Biology, New Orleans, LA, USA
| | - Suresh K Alahari
- Louisiana State University Health Science Center (LSUHSC), Biochemistry & Molecular Biology, New Orleans, LA, USA.
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17
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Mob4-dependent STRIPAK involves the chaperonin TRiC to coordinate myofibril and microtubule network growth. PLoS Genet 2022; 18:e1010287. [PMID: 35737712 PMCID: PMC9258817 DOI: 10.1371/journal.pgen.1010287] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Revised: 07/06/2022] [Accepted: 06/08/2022] [Indexed: 11/19/2022] Open
Abstract
Myofibrils of the skeletal muscle are comprised of sarcomeres that generate force by contraction when myosin-rich thick filaments slide past actin-based thin filaments. Surprisingly little is known about the molecular processes that guide sarcomere assembly in vivo, despite deficits within this process being a major cause of human disease. To overcome this knowledge gap, we undertook a forward genetic screen coupled with reverse genetics to identify genes required for vertebrate sarcomere assembly. In this screen, we identified a zebrafish mutant with a nonsense mutation in mob4. In Drosophila, mob4 has been reported to play a role in spindle focusing as well as neurite branching and in planarians mob4 was implemented in body size regulation. In contrast, zebrafish mob4geh mutants are characterised by an impaired actin biogenesis resulting in sarcomere defects. Whereas loss of mob4 leads to a reduction in the amount of myofibril, transgenic expression of mob4 triggers an increase. Further genetic analysis revealed the interaction of Mob4 with the actin-folding chaperonin TRiC, suggesting that Mob4 impacts on TRiC to control actin biogenesis and thus myofibril growth. Additionally, mob4geh features a defective microtubule network, which is in-line with tubulin being the second main folding substrate of TRiC. We also detected similar characteristics for strn3-deficient mutants, which confirmed Mob4 as a core component of STRIPAK and surprisingly implicates a role of the STRIPAK complex in sarcomerogenesis.
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18
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Non-canonical role of Hippo tumor suppressor serine/threonine kinase 3 STK3 in prostate cancer. Mol Ther 2022; 30:485-500. [PMID: 34450249 PMCID: PMC8753456 DOI: 10.1016/j.ymthe.2021.08.029] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 07/14/2021] [Accepted: 08/20/2021] [Indexed: 01/07/2023] Open
Abstract
Serine/threonine kinase 3 (STK3) is an essential member of the highly conserved Hippo tumor suppressor pathway that regulates Yes-associated protein 1 (YAP1) and TAZ. STK3 and its paralog STK4 initiate a phosphorylation cascade that regulates YAP1/TAZ inhibition and degradation, which is important for regulated cell growth and organ size. Deregulation of this pathway leads to hyperactivation of YAP1 in various cancers. Counter to the canonical tumor suppression role of STK3, we report that in the context of prostate cancer (PC), STK3 has a pro-tumorigenic role. Our investigation started with the observation that STK3, but not STK4, is frequently amplified in PC. Additionally, high STK3 expression is associated with decreased overall survival and positively correlates with androgen receptor (AR) activity in metastatic castrate-resistant PC. XMU-MP-1, an STK3/4 inhibitor, slowed cell proliferation, spheroid growth, and Matrigel invasion in multiple models. Genetic depletion of STK3 decreased proliferation in several PC cell lines. In a syngeneic allograft model, STK3 loss slowed tumor growth kinetics in vivo, and biochemical analysis suggests a mitotic growth arrest phenotype. To further probe the role of STK3 in PC, we identified and validated a new set of selective STK3 inhibitors, with enhanced kinase selectivity relative to XMU-MP-1, that inhibited tumor spheroid growth and invasion. Consistent with the canonical role, inhibition of STK3 induced cardiomyocyte growth and had chemoprotective effects. Our results indicate that STK3 has a non-canonical role in PC progression and that inhibition of STK3 may have a therapeutic potential for PC that merits further investigation.
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19
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Gundogdu R, Erdogan MK, Ditsiou A, Spanswick V, Garcia-Gomez JJ, Hartley JA, Esashi F, Hergovich A, Gomez V. hMOB2 deficiency impairs homologous recombination-mediated DNA repair and sensitises cancer cells to PARP inhibitors. Cell Signal 2021; 87:110106. [PMID: 34363951 PMCID: PMC8514680 DOI: 10.1016/j.cellsig.2021.110106] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Revised: 08/01/2021] [Accepted: 08/02/2021] [Indexed: 11/29/2022]
Abstract
Monopolar spindle-one binder (MOBs) proteins are evolutionarily conserved and contribute to various cellular signalling pathways. Recently, we reported that hMOB2 functions in preventing the accumulation of endogenous DNA damage and a subsequent p53/p21-dependent G1/S cell cycle arrest in untransformed cells. However, the question of how hMOB2 protects cells from endogenous DNA damage accumulation remained enigmatic. Here, we uncover hMOB2 as a regulator of double-strand break (DSB) repair by homologous recombination (HR). hMOB2 supports the phosphorylation and accumulation of the RAD51 recombinase on resected single-strand DNA (ssDNA) overhangs. Physiologically, hMOB2 expression supports cancer cell survival in response to DSB-inducing anti-cancer compounds. Specifically, loss of hMOB2 renders ovarian and other cancer cells more vulnerable to FDA-approved PARP inhibitors. Reduced MOB2 expression correlates with increased overall survival in patients suffering from ovarian carcinoma. Taken together, our findings suggest that hMOB2 expression may serve as a candidate stratification biomarker of patients for HR-deficiency targeted cancer therapies, such as PARP inhibitor treatments.
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Affiliation(s)
- Ramazan Gundogdu
- Department of Biology, Bingol University, Bingol 12000, Turkey; UCL Cancer Institute, University College London, London WC1E 6DD, UK.
| | - M Kadir Erdogan
- Department of Biology, Bingol University, Bingol 12000, Turkey
| | - Angeliki Ditsiou
- Department of Biochemistry and Biomedicine, University of Sussex, Brighton BN1 9QG, UK; UCL Cancer Institute, University College London, London WC1E 6DD, UK
| | | | | | - John A Hartley
- UCL Cancer Institute, University College London, London WC1E 6DD, UK
| | - Fumiko Esashi
- Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UK
| | - Alexander Hergovich
- UCL Cancer Institute, University College London, London WC1E 6DD, UK; Evotec France, Toulouse 31100, France
| | - Valenti Gomez
- UCL Cancer Institute, University College London, London WC1E 6DD, UK.
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20
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Resveratrol Inhibits Hepatic Stellate Cell Activation via the Hippo Pathway. Mediators Inflamm 2021; 2021:3399357. [PMID: 34690551 PMCID: PMC8528611 DOI: 10.1155/2021/3399357] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2021] [Revised: 08/28/2021] [Accepted: 09/18/2021] [Indexed: 12/13/2022] Open
Abstract
Liver fibrosis, which results from chronic liver injury due to factors such as chronic alcohol consumption, hepatitis virus infections, and immune attacks, is marked by excessive deposition of extracellular matrix (ECM). Resveratrol (Res), a polyphenol phytoalexin, has been demonstrated to show anti-inflammatory, antioxidative, antiproliferative, and chemopreventive activities. In recent years, Res has been found to inhibit liver fibrosis. Enhanced Hippo pathway activation has also been reported to inhibit tumor progression and liver fibrosis. In the present study, the role of the Hippo pathway in mediating the effects of Res on hepatic stellate cells (HSCs) was examined. We found that Res significantly suppresses HSC proliferation, reducing the cell index. Res induced HSC inactivation, reducing collagen deposition and α-smooth muscle actin (α-SMA) expression. In addition, Res contributed to HSC apoptosis, upregulating Bax and downregulating Bcl-2 expression. Notably, the Hippo pathway was involved in the Res-mediated suppression of HSC activation. Res enhanced the activation of the Hippo pathway and reduced yes-associated protein (YAP) and transcriptional coactivator with the PDZ-binding motif (TAZ) expression. Interestingly, the YAP overexpression inhibited Res-induced HSC inactivation and apoptosis. In conclusion, these results demonstrate that Res inhibits HSC activation, at least in part, via the Hippo pathway. The present study indicates a new antifibrotic mechanism of Res and provides novel insights into Hippo-mediated HSC apoptosis and HSC activation in liver fibrosis.
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21
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Rozengurt E, Eibl G. Crosstalk between KRAS, SRC and YAP Signaling in Pancreatic Cancer: Interactions Leading to Aggressive Disease and Drug Resistance. Cancers (Basel) 2021; 13:5126. [PMID: 34680275 PMCID: PMC8533944 DOI: 10.3390/cancers13205126] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Revised: 10/07/2021] [Accepted: 10/08/2021] [Indexed: 12/13/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC), the predominant form of pancreatic cancer, remains a devastating disease. The purpose of this review is to highlight recent literature on mechanistic and translational developments that advance our understanding of a complex crosstalk between KRAS, YAP and Src tyrosine kinase family (SFK) in PDAC development and maintenance. We discuss recent studies indicating the importance of RAS dimerization in signal transduction and new findings showing that the potent pro-oncogenic members of the SFK phosphorylate and inhibit RAS function. These surprising findings imply that RAS may not play a crucial role in maintaining certain subtypes of PDAC. In support of this interpretation, current evidence indicates that the survival of the basal-like subtype of PDAC is less dependent on RAS but relies, at least in part, on the activity of YAP/TAZ. Based on current evidence, we propose that SFK propels PDAC cells to a state of high metastasis, epithelial-mesenchymal transition (EMT) and reduced dependence on KRAS signaling, salient features of the aggressive basal-like/squamous subtype of PDAC. Strategies for PDAC treatment should consider the opposite effects of tyrosine phosphorylation on KRAS and SFK/YAP in the design of drug combinations that target these novel crosstalk mechanisms and overcome drug resistance.
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Affiliation(s)
- Enrique Rozengurt
- Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
| | - Guido Eibl
- Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA;
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22
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Wang M, Dai M, Wang D, Xiong W, Zeng Z, Guo C. The regulatory networks of the Hippo signaling pathway in cancer development. J Cancer 2021; 12:6216-6230. [PMID: 34539895 PMCID: PMC8425214 DOI: 10.7150/jca.62402] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Accepted: 08/15/2021] [Indexed: 01/14/2023] Open
Abstract
The Hippo signaling pathway is a relatively young tumor-related signaling pathway. Although it was discovered lately, research on it developed rapidly. The Hippo signaling pathway is closely relevant to the occurrence and development of tumors and the maintenance of organ size and other biological processes. This manuscript focuses on YAP, the core molecule of the Hippo signaling pathway, and discussion the upstream and downstream regulatory networks of the Hippo signaling pathway during tumorigenesis and development. It also summarizes the relevant drugs involved in this signaling pathway, which may be helpful to the development of targeted drugs for cancer therapy.
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Affiliation(s)
- Maonan Wang
- NHC Key Laboratory of Carcinogenesis, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, China
| | - Manli Dai
- Hunan Food and Drug Vocational College, Changsha 410036, China
| | - Dan Wang
- NHC Key Laboratory of Carcinogenesis, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, China
| | - Wei Xiong
- NHC Key Laboratory of Carcinogenesis, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, China
| | - Zhaoyang Zeng
- NHC Key Laboratory of Carcinogenesis, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, China
| | - Can Guo
- NHC Key Laboratory of Carcinogenesis, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, China
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23
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Zhu B, Qian W, Han C, Bai T, Hou X. Piezo 1 activation facilitates cholangiocarcinoma metastasis via Hippo/YAP signaling axis. MOLECULAR THERAPY. NUCLEIC ACIDS 2021; 24:241-252. [PMID: 33767919 PMCID: PMC7973248 DOI: 10.1016/j.omtn.2021.02.026] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/11/2020] [Accepted: 02/22/2021] [Indexed: 12/12/2022]
Abstract
Tumor metastasis is one of the major factors for the high mortality in cholangiocarcinoma (CCA), but its underlying mechanisms are not fully understood. Here, we report that Piezo-type mechanosensitive ion channel component 1 (Piezo 1) is detected to be significantly upregulated in CCA tissues, which is linked to a poor prognosis in patients, suggesting that Piezo 1 may act in a pro-metastatic role in CCA development. Piezo 1 is activated through 20% simulated physiological stretch, and deleting Piezo 1 impedes epithelial-to-mesenchymal transition (EMT) of CCA cells, as well as impairing their metastatic capacity in vitro and in vivo. Mechanistically, the activation of Piezo 1 results in large amounts of Yes-associated protein 1 (YAP) translocated into the nucleus from the cytoplasm, and thus the motility of CCA cells is significantly increased. These findings indicate that mechanical stimulation induces Piezo 1 activation, which might be involved in CCA metastasis via the Hippo/YAP signaling axis. Therefore, Piezo 1 and its downstream effectors may be a novel therapeutic target for CCA treatment.
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Affiliation(s)
- Biqiang Zhu
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Wei Qian
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Chaoqun Han
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Tao Bai
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Xiaohua Hou
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
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24
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Targeted Quantification of Phosphorylation Sites Identifies STRIPAK-Dependent Phosphorylation of the Hippo Pathway-Related Kinase SmKIN3. mBio 2021; 12:mBio.00658-21. [PMID: 33947760 PMCID: PMC8262875 DOI: 10.1128/mbio.00658-21] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
We showed recently that the germinal center kinase III (GCKIII) SmKIN3 from the fungus Sordaria macrospora is involved in sexual development and hyphal septation. Our recent extensive global proteome and phosphoproteome analysis revealed that SmKIN3 is a target of the striatin-interacting phosphatase and kinase (STRIPAK) multisubunit complex. Here, using protein samples from the wild type and three STRIPAK mutants, we applied absolute quantification by parallel-reaction monitoring (PRM) to analyze phosphorylation site occupancy in SmKIN3 and other septation initiation network (SIN) components, such as CDC7 and DBF2, as well as BUD4, acting downstream of SIN. For SmKIN3, we show that phosphorylation of S668 and S686 is decreased in mutants lacking distinct subunits of STRIPAK, while a third phosphorylation site, S589, was not affected. We constructed SmKIN3 mutants carrying phospho-mimetic and phospho-deficient codons for phosphorylation sites S589, S668, and S686. Investigation of hyphae in a ΔSmkin3 strain complemented by the S668 and S686 mutants showed a hyper-septation phenotype, which was absent in the wild type, the ΔSmkin3 strain complemented with the wild-type gene, and the S589 mutant. Furthermore, localization studies with SmKIN3 phosphorylation variants and STRIPAK mutants showed that SmKIN3 preferentially localizes at the terminal septa, which is distinctly different from the localization of the wild-type strains. We conclude that STRIPAK-dependent phosphorylation of SmKIN3 has an impact on controlled septum formation and on the time-dependent localization of SmKIN3 on septa at the hyphal tip. Thus, STRIPAK seems to regulate SmKIN3, as well as DBF2 and BUD4 phosphorylation, affecting septum formation.
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IQGAP1 Is a Scaffold of the Core Proteins of the Hippo Pathway and Negatively Regulates the Pro-Apoptotic Signal Mediated by This Pathway. Cells 2021; 10:cells10020478. [PMID: 33672268 PMCID: PMC7926663 DOI: 10.3390/cells10020478] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2020] [Revised: 02/13/2021] [Accepted: 02/20/2021] [Indexed: 12/21/2022] Open
Abstract
The Hippo pathway regulates a complex signalling network which mediates several biological functions including cell proliferation, organ size and apoptosis. Several scaffold proteins regulate the crosstalk of the members of the pathway with other signalling pathways and play an important role in the diverse output controlled by this pathway. In this study we have identified the scaffold protein IQGAP1 as a novel interactor of the core kinases of the Hippo pathway, MST2 and LATS1. Our results indicate that IQGAP1 scaffolds MST2 and LATS1 supresses their kinase activity and YAP1-dependent transcription. Additionally, we show that IQGAP1 is a negative regulator of the non-canonical pro-apoptotic pathway and may enable the crosstalk between this pathway and the ERK and AKT signalling modules. Our data also show that bile acids regulate the IQGAP1-MST2-LATS1 signalling module in hepatocellular carcinoma cells, which could be necessary for the inhibition of MST2-dependent apoptosis and hepatocyte transformation.
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Zhou PM, Liang Y, Mei J, Liao HZ, Wang P, Hu K, Chen LQ, Zhang XQ, Ye D. The Arabidopsis AGC kinases NDR2/4/5 interact with MOB1A/1B and play important roles in pollen development and germination. THE PLANT JOURNAL : FOR CELL AND MOLECULAR BIOLOGY 2021; 105:1035-1052. [PMID: 33215783 DOI: 10.1111/tpj.15085] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/09/2020] [Revised: 09/29/2020] [Accepted: 10/21/2020] [Indexed: 06/11/2023]
Abstract
Pollen formation and pollen tube growth are essential for the delivery of male gametes into the female embryo sac for double fertilization. Little is known about the mechanisms that regulate the late developmental process of pollen formation and pollen germination. In this study, we characterized a group of Arabidopsis AGC kinase proteins, NDR2/4/5, involved in pollen development and pollen germination. The NDR2/4/5 genes are mainly expressed in pollen grains at the late developmental stages and in pollen tubes. They function redundantly in pollen formation and pollen germination. At the tricellular stages, the ndr2 ndr4 ndr5 mutant pollen grains exhibit an abnormal accumulation of callose, precocious germination and burst in anthers, leading to a drastic reduction in fertilization and a reduced seed set. NDR2/4/5 proteins can interact with another group of proteins (MOB1A/1B) homologous to the MOB proteins from the Hippo signaling pathway in yeast and animals. The Arabidopsis mob1a mob1b mutant pollen grains also have a phenotype similar to that of ndr2 ndr4 ndr5 pollen grains. These results provide new evidence demonstrating that the Hippo signaling components are conserved in plants and play important roles in sexual plant reproduction.
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Affiliation(s)
- Peng-Min Zhou
- State Key Laboratory of Plant Physiology and Biochemistry, College of Biological Sciences, China Agricultural University, Beijing, China
| | - Yan Liang
- State Key Laboratory of Plant Physiology and Biochemistry, College of Biological Sciences, China Agricultural University, Beijing, China
| | - Juan Mei
- State Key Laboratory of Plant Physiology and Biochemistry, College of Biological Sciences, China Agricultural University, Beijing, China
| | - Hong-Ze Liao
- State Key Laboratory of Plant Physiology and Biochemistry, College of Biological Sciences, China Agricultural University, Beijing, China
| | - Pu Wang
- State Key Laboratory of Plant Physiology and Biochemistry, College of Biological Sciences, China Agricultural University, Beijing, China
| | - Ke Hu
- State Key Laboratory of Plant Physiology and Biochemistry, College of Biological Sciences, China Agricultural University, Beijing, China
| | - Li-Qun Chen
- State Key Laboratory of Plant Physiology and Biochemistry, College of Biological Sciences, China Agricultural University, Beijing, China
| | - Xue-Qin Zhang
- State Key Laboratory of Plant Physiology and Biochemistry, College of Biological Sciences, China Agricultural University, Beijing, China
| | - De Ye
- State Key Laboratory of Plant Physiology and Biochemistry, College of Biological Sciences, China Agricultural University, Beijing, China
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Delgado ILS, Carmona B, Nolasco S, Santos D, Leitão A, Soares H. MOB: Pivotal Conserved Proteins in Cytokinesis, Cell Architecture and Tissue Homeostasis. BIOLOGY 2020; 9:biology9120413. [PMID: 33255245 PMCID: PMC7761452 DOI: 10.3390/biology9120413] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Revised: 11/20/2020] [Accepted: 11/21/2020] [Indexed: 01/08/2023]
Abstract
The MOB family proteins are constituted by highly conserved eukaryote kinase signal adaptors that are often essential both for cell and organism survival. Historically, MOB family proteins have been described as kinase activators participating in Hippo and Mitotic Exit Network/ Septation Initiation Network (MEN/SIN) signaling pathways that have central roles in regulating cytokinesis, cell polarity, cell proliferation and cell fate to control organ growth and regeneration. In metazoans, MOB proteins act as central signal adaptors of the core kinase module MST1/2, LATS1/2, and NDR1/2 kinases that phosphorylate the YAP/TAZ transcriptional co-activators, effectors of the Hippo signaling pathway. More recently, MOBs have been shown to also have non-kinase partners and to be involved in cilia biology, indicating that its activity and regulation is more diverse than expected. In this review, we explore the possible ancestral role of MEN/SIN pathways on the built-in nature of a more complex and functionally expanded Hippo pathway, by focusing on the most conserved components of these pathways, the MOB proteins. We discuss the current knowledge of MOBs-regulated signaling, with emphasis on its evolutionary history and role in morphogenesis, cytokinesis, and cell polarity from unicellular to multicellular organisms.
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Affiliation(s)
- Inês L. S. Delgado
- CIISA-Centro de Investigação Interdisciplinar em Sanidade Animal, Faculdade de Medicina Veterinária, Universidade de Lisboa, 1300-477 Lisboa, Portugal or (I.L.S.D.); or (S.N.); (D.S.); (A.L.)
- Faculdade de Medicina Veterinária, Universidade Lusófona de Humanidades e Tecnologias, 1749-024 Lisboa, Portugal
| | - Bruno Carmona
- Escola Superior de Tecnologia da Saúde de Lisboa, Instituto Politécnico de Lisboa, 1990-096 Lisboa, Portugal; or
- Centro de Química Estrutural–Faculdade de Ciências da Universidade de Lisboa, 1749-016 Lisboa, Portugal
| | - Sofia Nolasco
- CIISA-Centro de Investigação Interdisciplinar em Sanidade Animal, Faculdade de Medicina Veterinária, Universidade de Lisboa, 1300-477 Lisboa, Portugal or (I.L.S.D.); or (S.N.); (D.S.); (A.L.)
- Escola Superior de Tecnologia da Saúde de Lisboa, Instituto Politécnico de Lisboa, 1990-096 Lisboa, Portugal; or
| | - Dulce Santos
- CIISA-Centro de Investigação Interdisciplinar em Sanidade Animal, Faculdade de Medicina Veterinária, Universidade de Lisboa, 1300-477 Lisboa, Portugal or (I.L.S.D.); or (S.N.); (D.S.); (A.L.)
| | - Alexandre Leitão
- CIISA-Centro de Investigação Interdisciplinar em Sanidade Animal, Faculdade de Medicina Veterinária, Universidade de Lisboa, 1300-477 Lisboa, Portugal or (I.L.S.D.); or (S.N.); (D.S.); (A.L.)
| | - Helena Soares
- Escola Superior de Tecnologia da Saúde de Lisboa, Instituto Politécnico de Lisboa, 1990-096 Lisboa, Portugal; or
- Centro de Química Estrutural–Faculdade de Ciências da Universidade de Lisboa, 1749-016 Lisboa, Portugal
- Correspondence: or
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Du C, Lv C, Feng Y, Yu S. Activation of the KDM5A/miRNA-495/YTHDF2/m6A-MOB3B axis facilitates prostate cancer progression. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2020; 39:223. [PMID: 33087165 PMCID: PMC7576758 DOI: 10.1186/s13046-020-01735-3] [Citation(s) in RCA: 63] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Accepted: 08/03/2020] [Indexed: 01/13/2023]
Abstract
Background Accumulating evidence supports that lysine-specific demethylase 5 (KDM5) family members act as oncogenic drivers. This study was performed to elucidate the potential effects of KDM5A on prostate cancer (PCa) progression via the miR-495/YTHDF2/m6A-MOB3B axis. Methods The expression of KDM5A, miR-495, YTHDF2 and MOB3B was validated in human PCa tissues and cell lines. Ectopic expression and knockdown experiments were developed in PCa cells to evaluate their effects on PCa cell proliferation, migration, invasion and apoptosis. Mechanistic insights into the interaction among KDM5A, miR-495, YTHDF2 and MOB3B were obtained after dual luciferase reporter, ChIP, and PAR-CLIP assays. Me-RIP assay was used to determine m6A modification level of MOB3B mRNA in PCa cells. Mouse xenograft models of PCa cells were also established to monitor the tumor growth. Results KDM5A was highly expressed in human PCa tissues and cell lines. Upregulated KDM5A stimulated PCa cell proliferation, migration and invasion, but reduced cell apoptosis. Mechanistically, KDM5A, as a H3K4me3 demethylase, bound to the miR-495 promoter, which led to inhibition of its transcription and expression. As a target of miR-495, YTHDF2 could inhibit MOB3B expression by recognizing m6A modification of MOB3B mRNA and inducing mRNA degradation. Furthermore, KDM5A was found to downregulate MOB3B expression, consequently augmenting PCa cell proliferation, migration and invasion in vitro and promoting tumor growth in vivo via the miR-495/YTHDF2 axis. Conclusion In summary, our study highlights the potential of histone demethylase KDM5A activity in enhancing PCa progression, and suggests KDM5A as a promising target for PCa treatment. Supplementary information Supplementary information accompanies this paper at 10.1186/s13046-020-01735-3.
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Affiliation(s)
- Chen Du
- Department of Urology Surgery, Harbin Medical University Cancer Hospital, No. 150, Haping Road, Nangang District, Harbin, 150000, Heilongjiang Province, People's Republic of China.
| | - Caihong Lv
- Department of Laboratory, the Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001, People's Republic of China
| | - Yue Feng
- Department of Urology Surgery, Harbin Medical University Cancer Hospital, No. 150, Haping Road, Nangang District, Harbin, 150000, Heilongjiang Province, People's Republic of China
| | - Siwen Yu
- Department of Urology Surgery, Harbin Medical University Cancer Hospital, No. 150, Haping Road, Nangang District, Harbin, 150000, Heilongjiang Province, People's Republic of China
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Ando N, Tanaka K, Otsubo K, Toyokawa G, Ikematsu Y, Ide M, Yoneshima Y, Iwama E, Inoue H, Ijichi K, Tagawa T, Nakanishi Y, Okamoto I. Association of Mps one binder kinase activator 1 (MOB1) expression with poor disease-free survival in individuals with non-small cell lung cancer. Thorac Cancer 2020; 11:2830-2839. [PMID: 32841529 PMCID: PMC7529568 DOI: 10.1111/1759-7714.13608] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Revised: 07/12/2020] [Accepted: 07/21/2020] [Indexed: 11/30/2022] Open
Abstract
Background Mps one binder kinase activator 1 (MOB1) is a core component of the Hippo signaling pathway and has been implicated as a tumor suppressor. Here, we evaluated the possible relationship of MOB1 expression in non‐small cell lung cancer (NSCLC) to prognosis. Methods We retrospectively analyzed 205 lung adenocarcinoma patients treated at Kyushu University Hospital between November 2007 and October 2012. MOB1 expression in tumor cells of surgical specimens was evaluated by immunohistochemistry. Invasive activity of NSCLC cell lines in vitro was measured with a transwell assay. Results Expression of MOB1 was classified as high in 105 of the 205 (51.2%) tumor specimens, and such high expression was significantly associated with poor disease‐free survival (P = 0.0161). Among the various clinicopathologic parameters examined, high MOB1 expression was significantly associated only with intratumoral vascular invasion (P = 0.0005). Multivariate analysis also identified high MOB1 expression as a significant independent risk factor for disease‐free survival (P = 0.0319). The invasiveness of H1299 cells in vitro was increased or attenuated by overexpression or knockdown of MOB1, respectively. Conclusions Our results suggest that MOB1 might promote early recurrence of NSCLC by increasing vascular invasion by tumor cells. Key points Significant findings of the study We found that high MOB1 expression in surgical specimens of lung adenocarcinoma was associated with poor disease‐free survival and with intratumoral vascular invasion. MOB1 expression also promoted the invasiveness of NSCLC cells in vitro. What this study adds Our results thus suggest that high MOB1 expression is a risk factor for early postoperative recurrence in lung adenocarcinoma.
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Affiliation(s)
- Nobuhisa Ando
- Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Kentaro Tanaka
- Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Kohei Otsubo
- Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Gouji Toyokawa
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yuki Ikematsu
- Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Maako Ide
- Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yasuto Yoneshima
- Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Eiji Iwama
- Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Hiroyuki Inoue
- Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Kayo Ijichi
- Pathophysiological and Experimental Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Tetsuzo Tagawa
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yoichi Nakanishi
- Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.,Kitakyushu City Hospital Organization, Fukuoka, Japan
| | - Isamu Okamoto
- Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
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30
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Jiang K, Yao G, Hu L, Yan Y, Liu J, Shi J, Chang Y, Zhang Y, Liang D, Shen D, Zhang G, Meng S, Piao H. MOB2 suppresses GBM cell migration and invasion via regulation of FAK/Akt and cAMP/PKA signaling. Cell Death Dis 2020; 11:230. [PMID: 32286266 PMCID: PMC7156523 DOI: 10.1038/s41419-020-2381-8] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2019] [Revised: 01/30/2020] [Accepted: 01/31/2020] [Indexed: 12/20/2022]
Abstract
Mps one binder 2 (MOB2) regulates the NDR kinase family, however, whether and how it is implicated in cancer remain unknown. Here we show that MOB2 functions as a tumor suppressor in glioblastoma (GBM). Analysis of MOB2 expression in glioma patient specimens and bioinformatic analyses of public datasets revealed that MOB2 was downregulated at both mRNA and protein levels in GBM. Ectopic MOB2 expression suppressed, while depletion of MOB2 enhanced, the malignant phenotypes of GBM cells, such as clonogenic growth, anoikis resistance, and formation of focal adhesions, migration, and invasion. Moreover, depletion of MOB2 increased, while overexpression of MOB2 decreased, GBM cell metastasis in a chick chorioallantoic membrane model. Overexpression of MOB2-mediated antitumor effects were further confirmed in mouse xenograft models. Mechanistically, MOB2 negatively regulated the FAK/Akt pathway involving integrin. Notably, MOB2 interacted with and promoted PKA signaling in a cAMP-dependent manner. Furthermore, the cAMP activator Forskolin increased, while the PKA inhibitor H89 decreased, MOB2 expression in GBM cells. Functionally, MOB2 contributed to the cAMP/PKA signaling-regulated inactivation of FAK/Akt pathway and inhibition of GBM cell migration and invasion. Collectively, these findings suggest a role of MOB2 as a tumor suppressor in GBM via regulation of FAK/Akt signaling. Additionally, we uncover MOB2 as a novel regulator in cAMP/PKA signaling. Given that small compounds targeting FAK and cAMP pathway have been tested in clinical trials, we suggest that interference with MOB2 expression and function may support a theoretical and therapeutic basis for applications of these compounds.
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Affiliation(s)
- Ke Jiang
- Department of Neurosurgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, China.,Institute of Cancer Stem Cell, Dalian Medical University Cancer Center, 9 Lvshun Road South, 116044, Dalian, China
| | - Gang Yao
- Institute of Cancer Stem Cell, Dalian Medical University Cancer Center, 9 Lvshun Road South, 116044, Dalian, China
| | - Lulu Hu
- Institute of Cancer Stem Cell, Dalian Medical University Cancer Center, 9 Lvshun Road South, 116044, Dalian, China
| | - Yumei Yan
- The First Department of Ultrasound, the First Affiliated Hospital to Dalian Medical University, No. 222 Zhongshan Road, 116021, Dalian, China
| | - Jia Liu
- Department of Neurosurgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, China
| | - Ji Shi
- Department of Neurosurgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, China
| | - Youwei Chang
- Department of Neurosurgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, China
| | - Ye Zhang
- Department of Neurosurgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, China
| | - Dapeng Liang
- Institute of Cancer Stem Cell, Dalian Medical University Cancer Center, 9 Lvshun Road South, 116044, Dalian, China
| | - Dachuan Shen
- Department of Oncology, Affiliated Zhongshan Hospital of Dalian University, 116004, Dalian, China
| | - Guirong Zhang
- Central laboratory, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, China.
| | - Songshu Meng
- Institute of Cancer Stem Cell, Dalian Medical University Cancer Center, 9 Lvshun Road South, 116044, Dalian, China.
| | - Haozhe Piao
- Department of Neurosurgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, China.
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Ye X, Ong N, An H, Zheng Y. The Emerging Roles of NDR1/2 in Infection and Inflammation. Front Immunol 2020; 11:534. [PMID: 32265942 PMCID: PMC7105721 DOI: 10.3389/fimmu.2020.00534] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2019] [Accepted: 03/09/2020] [Indexed: 12/28/2022] Open
Abstract
The nuclear Dbf2-related (NDR) kinases NDR1 and NDR2 belong to the NDR/LATS (large tumor suppressor) subfamily in the Hippo signaling pathway. They are highly conserved from yeast to humans. It is well-known that NDR1/2 control important cellular processes, such as morphological changes, centrosome duplication, cell proliferation, and apoptosis. Recent studies revealed that NDR1/2 also play important roles in the regulation of infection and inflammation. In this review, we summarized the roles of NDR1/2 in the modulation of inflammation induced by cytokines and innate immune response against the infection of bacteria and viruses, emphasizing on how NDR1/2 regulate signaling transduction through Hippo pathway-dependent and -independent manners.
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Affiliation(s)
- Xiaolan Ye
- Center for Traditional Chinese Medicine and Immunology Research, School of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Naomi Ong
- Center for Traditional Chinese Medicine and Immunology Research, School of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Huazhang An
- Center for Translational Medicine, Clinical Cancer Institute, Second Military Medical University, Shanghai, China
| | - Yuejuan Zheng
- Center for Traditional Chinese Medicine and Immunology Research, School of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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Duhart JC, Raftery LA. Mob Family Proteins: Regulatory Partners in Hippo and Hippo-Like Intracellular Signaling Pathways. Front Cell Dev Biol 2020; 8:161. [PMID: 32266255 DOI: 10.3389/fcell.2020.00161/full] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2019] [Accepted: 02/28/2020] [Indexed: 05/26/2023] Open
Abstract
Studies in yeast first delineated the function of Mob proteins in kinase pathways that regulate cell division and shape; in multicellular eukaryotes Mobs regulate tissue growth and morphogenesis. In animals, Mobs are adaptors in Hippo signaling, an intracellular signal-transduction pathway that restricts growth, impacting the development and homeostasis of animal organs. Central to Hippo signaling are the Nuclear Dbf2-Related (NDR) kinases, Warts and LATS1 and LATS2, in flies and mammals, respectively. A second Hippo-like signaling pathway has been uncovered in animals, which regulates cell and tissue morphogenesis. Central to this emergent pathway are the NDR kinases, Tricornered, STK38, and STK38L. In Hippo signaling, NDR kinase activation is controlled by three activating interactions with a conserved set of proteins. This review focuses on one co-activator family, the highly conserved, non-catalytic Mps1-binder-related (Mob) proteins. In this context, Mobs are allosteric activators of NDR kinases and adaptors that contribute to assembly of multiprotein NDR kinase activation complexes. In multicellular eukaryotes, the Mob family has expanded relative to model unicellular yeasts; accumulating evidence points to Mob functional diversification. A striking example comes from the most sequence-divergent class of Mobs, which are components of the highly conserved Striatin Interacting Phosphatase and Kinase (STRIPAK) complex, that antagonizes Hippo signaling. Mobs stand out for their potential to modulate the output from Hippo and Hippo-like kinases, through their roles both in activating NDR kinases and in antagonizing upstream Hippo or Hippo-like kinase activity. These opposing Mob functions suggest that they coordinate the relative activities of the Tricornered/STK38/STK38L and Warts/LATS kinases, and thus have potential to assemble nodes for pathway signaling output. We survey the different facets of Mob-dependent regulation of Hippo and Hippo-like signaling and highlight open questions that hinge on unresolved aspects of Mob functions.
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Affiliation(s)
- Juan Carlos Duhart
- School of Life Sciences, University of Nevada, Las Vegas, Las Vegas, NV, United States
| | - Laurel A Raftery
- School of Life Sciences, University of Nevada, Las Vegas, Las Vegas, NV, United States
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Duhart JC, Raftery LA. Mob Family Proteins: Regulatory Partners in Hippo and Hippo-Like Intracellular Signaling Pathways. Front Cell Dev Biol 2020; 8:161. [PMID: 32266255 PMCID: PMC7096357 DOI: 10.3389/fcell.2020.00161] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2019] [Accepted: 02/28/2020] [Indexed: 12/16/2022] Open
Abstract
Studies in yeast first delineated the function of Mob proteins in kinase pathways that regulate cell division and shape; in multicellular eukaryotes Mobs regulate tissue growth and morphogenesis. In animals, Mobs are adaptors in Hippo signaling, an intracellular signal-transduction pathway that restricts growth, impacting the development and homeostasis of animal organs. Central to Hippo signaling are the Nuclear Dbf2-Related (NDR) kinases, Warts and LATS1 and LATS2, in flies and mammals, respectively. A second Hippo-like signaling pathway has been uncovered in animals, which regulates cell and tissue morphogenesis. Central to this emergent pathway are the NDR kinases, Tricornered, STK38, and STK38L. In Hippo signaling, NDR kinase activation is controlled by three activating interactions with a conserved set of proteins. This review focuses on one co-activator family, the highly conserved, non-catalytic Mps1-binder-related (Mob) proteins. In this context, Mobs are allosteric activators of NDR kinases and adaptors that contribute to assembly of multiprotein NDR kinase activation complexes. In multicellular eukaryotes, the Mob family has expanded relative to model unicellular yeasts; accumulating evidence points to Mob functional diversification. A striking example comes from the most sequence-divergent class of Mobs, which are components of the highly conserved Striatin Interacting Phosphatase and Kinase (STRIPAK) complex, that antagonizes Hippo signaling. Mobs stand out for their potential to modulate the output from Hippo and Hippo-like kinases, through their roles both in activating NDR kinases and in antagonizing upstream Hippo or Hippo-like kinase activity. These opposing Mob functions suggest that they coordinate the relative activities of the Tricornered/STK38/STK38L and Warts/LATS kinases, and thus have potential to assemble nodes for pathway signaling output. We survey the different facets of Mob-dependent regulation of Hippo and Hippo-like signaling and highlight open questions that hinge on unresolved aspects of Mob functions.
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Affiliation(s)
| | - Laurel A. Raftery
- School of Life Sciences, University of Nevada, Las Vegas, Las Vegas, NV, United States
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34
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Rausch V, Hansen CG. The Hippo Pathway, YAP/TAZ, and the Plasma Membrane. Trends Cell Biol 2019; 30:32-48. [PMID: 31806419 DOI: 10.1016/j.tcb.2019.10.005] [Citation(s) in RCA: 176] [Impact Index Per Article: 29.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2019] [Revised: 10/13/2019] [Accepted: 10/14/2019] [Indexed: 12/14/2022]
Abstract
The plasma membrane allows the cell to sense and adapt to changes in the extracellular environment by relaying external inputs via intracellular signaling networks. One central cellular signaling pathway is the Hippo pathway, which regulates homeostasis and plays chief roles in carcinogenesis and regenerative processes. Recent studies have found that mechanical stimuli and diffusible chemical components can regulate the Hippo pathway primarily through receptors embedded in the plasma membrane. Morphologically defined structures within the plasma membrane, such as cellular junctions, focal adhesions, primary cilia, caveolae, clathrin-coated pits, and plaques play additional key roles. Here, we discuss recent evidence highlighting the importance of these specialized plasma membrane domains in cellular feedback via the Hippo pathway.
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Affiliation(s)
- Valentina Rausch
- Centre for Inflammation Research, University of Edinburgh, Queen's Medical Research Institute, Edinburgh bioQuarter, 47 Little France Crescent, Edinburgh EH16 4TJ, UK; Institute for Regeneration and Repair, University of Edinburgh, Edinburgh bioQuarter, 5 Little France Drive, Edinburgh EH16 4UU, UK
| | - Carsten G Hansen
- Centre for Inflammation Research, University of Edinburgh, Queen's Medical Research Institute, Edinburgh bioQuarter, 47 Little France Crescent, Edinburgh EH16 4TJ, UK; Institute for Regeneration and Repair, University of Edinburgh, Edinburgh bioQuarter, 5 Little France Drive, Edinburgh EH16 4UU, UK.
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Special Issue on "Disease and the Hippo Pathway". Cells 2019; 8:cells8101179. [PMID: 31575050 PMCID: PMC6830332 DOI: 10.3390/cells8101179] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2019] [Accepted: 09/27/2019] [Indexed: 11/27/2022] Open
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