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Chen SL, Wang GP, Shi DR, Yao SH, Chen KD, Yao HP. RON in hepatobiliary and pancreatic cancers: Pathogenesis and potential therapeutic targets. World J Gastroenterol 2021; 27:2507-2520. [PMID: 34092972 PMCID: PMC8160627 DOI: 10.3748/wjg.v27.i20.2507] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 03/04/2021] [Accepted: 04/09/2021] [Indexed: 02/06/2023] Open
Abstract
The receptor protein tyrosine kinase RON belongs to the c-MET proto-oncogene family. Research has shown that RON has a role in cancer pathogenesis, which places RON on the frontline of the development of novel cancer therapeutic strategies. Hepatobiliary and pancreatic (HBP) cancers have a poor prognosis, being reported as having higher rates of cancer-related death. Therefore, to combat these malignant diseases, the mechanism underlying the aberrant expression and signaling of RON in HBP cancer pathogenesis, and the development of RON as a drug target for therapeutic intervention should be investigated. Abnormal RON expression and signaling have been identified in HBP cancers, and also act as tumorigenic determinants for HBP cancer malignant behaviors. In addition, RON is emerging as an important mediator of the clinical prognosis of HBP cancers. Thus, not only is RON significant in HBP cancers, but also RON-targeted therapeutics could be developed to treat these cancers, for example, therapeutic monoclonal antibodies and small-molecule inhibitors. Among them, antibody-drug conjugates have become increasingly popular in current research and their potential as novel anti-cancer biotherapeutics will be determined in future clinical trials.
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Affiliation(s)
- Shao-Long Chen
- Shulan International Medical College, Zhejiang Shuren University, Hangzhou 310000, Zhejiang Province, China
| | - Guo-Ping Wang
- Department of Surgical Oncology, The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou 310000, Zhejiang Province, China
| | - Dan-Rong Shi
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310000, Zhejiang Province, China
| | - Shu-Hao Yao
- Department of Stomatology, Wenzhou Medical University Renji College, Wenzhou 325035, Zhejiang Province, China
| | - Ke-Da Chen
- Shulan International Medical College, Zhejiang Shuren University, Hangzhou 310000, Zhejiang Province, China
| | - Hang-Ping Yao
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310000, Zhejiang Province, China
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Faham N, Welm AL. RON Signaling Is a Key Mediator of Tumor Progression in Many Human Cancers. COLD SPRING HARBOR SYMPOSIA ON QUANTITATIVE BIOLOGY 2017; 81:177-188. [PMID: 28057847 DOI: 10.1101/sqb.2016.81.031377] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
With an increasing body of literature covering RON receptor tyrosine kinase function in different types of human cancers, it is becoming clear that RON has prominent roles in both cancer cells and in the tumor-associated microenvironment. RON not only activates several oncogenic signaling pathways in cancer cells, leading to more aggressive behavior, but also promotes an immunosuppressive, alternatively activated phenotype in macrophages and limits the antitumor immune response. These two unique functions of this oncogene, the strong correlation between RON expression and poor outcomes in cancer, and the high tolerability of a new RON inhibitor make it an exciting therapeutic target, the blocking of which offers an advantage toward improving the survival of cancer patients. Here, we discuss recent findings on the role of RON signaling in cancer progression and its potential in cancer therapy.
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Affiliation(s)
- Najme Faham
- Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah 84112
| | - Alana L Welm
- Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah 84112
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Karimi MA, Aguilar O, Zou B, Bachmann MH, Carlyle JR, Baldwin CL, Kambayashi T. A truncated human NKG2D splice isoform negatively regulates NKG2D-mediated function. THE JOURNAL OF IMMUNOLOGY 2014; 193:2764-2771. [PMID: 25092887 DOI: 10.4049/jimmunol.1400920] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Natural killer group 2, member D (NKG2D) is a stimulatory receptor expressed by NK cells and a subset of T cells. NKG2D is crucial in diverse aspects of innate and adaptive immune functions. In this study, we characterize a novel splice variant of human NKG2D that encodes a truncated receptor lacking the ligand-binding ectodomain. This truncated NKG2D (NKG2D(TR)) isoform was detected in primary human NK and CD8(+) T cells. Overexpression of NKG2D(TR) severely attenuated cell killing and IFN-γ release mediated by full-length NKG2D (NKG2D(FL)). In contrast, specific knockdown of endogenously expressed NKG2D(TR) enhanced NKG2D-mediated cytotoxicity, suggesting that NKG2D(TR) is a negative regulator of NKG2D(FL). Biochemical studies demonstrated that NKG2D(TR) was bound to DNAX-activated protein of 10 kDa (DAP10) and interfered with the interaction of DAP10 with NKG2D(FL). In addition, NKG2D(TR) associated with NKG2D(FL), which led to forced intracellular retention, resulting in decreased surface NKG2D expression. Taken together, these data suggest that competitive interference of NKG2D/DAP10 complexes by NKG2D(TR) constitutes a novel mechanism for regulation of NKG2D-mediated function in human CD8(+) T cells and NK cells.
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Affiliation(s)
- Mobin A Karimi
- Department of Veterinary & Animal Sciences/Immunology, University of Massachusetts, Amherst, MA.,Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA
| | - Oscar Aguilar
- Department of Immunology, University of Toronto, Toronto, Canada
| | - Baixiang Zou
- Department of Veterinary & Animal Sciences/Immunology, University of Massachusetts, Amherst, MA
| | - Michael H Bachmann
- Department of Pediatrics, Stanford University School of Medicine, Stanford, CA
| | - James R Carlyle
- Department of Immunology, University of Toronto, Toronto, Canada
| | - Cynthia L Baldwin
- Department of Veterinary & Animal Sciences/Immunology, University of Massachusetts, Amherst, MA
| | - Taku Kambayashi
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA
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Wang X, Yennawar N, Hankey PA. Autoinhibition of the Ron receptor tyrosine kinase by the juxtamembrane domain. Cell Commun Signal 2014; 12:28. [PMID: 24739671 PMCID: PMC4021555 DOI: 10.1186/1478-811x-12-28] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2013] [Accepted: 02/05/2014] [Indexed: 01/21/2023] Open
Abstract
Background The Ron receptor tyrosine kinase (RTK) has been implicated in the progression of a number of carcinomas, thus understanding the regulatory mechanisms governing its activity is of potential therapeutic significance. A critical role for the juxtamembrane domain in regulating RTK activity is emerging, however the mechanism by which this regulation occurs varies considerably from receptor to receptor. Results Unlike other RTKs described to date, tyrosines in the juxtamembrane domain of Ron are inconsequential for receptor activation. Rather, we have identified an acidic region in the juxtamembrane domain of Ron that plays a central role in promoting receptor autoinhibition. Furthermore, our studies demonstrate that phosphorylation of Y1198 in the kinase domain promotes Ron activation, likely by relieving the inhibitory constraints imposed by the juxtamembrane domain. Conclusions Taken together, our experimental data and molecular modeling provide a better understanding of the mechanisms governing Ron activation, which will lay the groundwork for the development of novel therapeutic approaches for targeting Ron in human malignancies.
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Affiliation(s)
| | | | - Pamela A Hankey
- Graduate Program in Cell and Developmental Biology, The Pennsylvania State University, University Park, PA 16802, USA.
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Wang MH, Zhang R, Zhou YQ, Yao HP. Pathogenesis of RON receptor tyrosine kinase in cancer cells: activation mechanism, functional crosstalk, and signaling addiction. J Biomed Res 2013; 27:345-56. [PMID: 24086167 PMCID: PMC3783819 DOI: 10.7555/jbr.27.20130038] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2013] [Accepted: 05/27/2013] [Indexed: 12/15/2022] Open
Abstract
The RON receptor tyrosine kinase, a member of the MET proto-oncogene family, is a pathogenic factor implicated in tumor malignancy. Specifically, aberrations in RON signaling result in increased cancer cell growth, survival, invasion, angiogenesis, and drug resistance. Biochemical events such as ligand binding, receptor overexpression, generation of structure-defected variants, and point mutations in the kinase domain contribute to RON signaling activation. Recently, functional crosstalk between RON and signaling proteins such as MET and EFGR has emerged as an additional mechanism for RON activation, which is critical for tumorigenic development. The RON signaling crosstalk acts either as a regulatory feedback loop that strengthens or enhances tumorigenic phenotype of cancer cells or serves as a signaling compensatory pathway providing a growth/survival advantage for cancer cells to escape targeted therapy. Moreover, viral oncoproteins derived from Friend leukemia or Epstein-Barr viruses interact with RON to drive viral oncogenesis. In cancer cells, RON signaling is integrated into cellular signaling network essential for cancer cell growth and survival. These activities provide the molecular basis of targeting RON for cancer treatment. In this review, we will discuss recent data that uncover the mechanisms of RON activation in cancer cells, review evidence of RON signaling crosstalk relevant to cancer malignancy, and emphasize the significance of the RON signaling addiction by cancer cells for tumor therapy. Understanding aberrant RON signaling will not only provide insight into the mechanisms of tumor pathogenesis, but also lead to the development of novel strategies for molecularly targeted cancer treatment.
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Affiliation(s)
- Ming-Hai Wang
- Cancer Biology Research Center, ; Department of Biomedical Sciences, and
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Abstract
Since the discovery of MSP (macrophage-stimulating protein; also known as MST1 and hepatocyte growth factor-like (HGFL)) as the ligand for the receptor tyrosine kinase RON (also known as MST1R) in the early 1990s, the roles of this signalling axis in cancer pathogenesis has been extensively studied in various model systems. Both in vitro and in vivo evidence has revealed that MSP-RON signalling is important for the invasive growth of different types of cancers. Currently, small-molecule inhibitors and antibodies blocking RON signalling are under investigation. Substantial responses have been achieved in human tumour xenograft models, laying the foundation for clinical validation. In this Review, we discuss recent advances that demonstrate the importance of MSP-RON signalling in cancer and its potential as a therapeutic target.
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Affiliation(s)
- Hang-Ping Yao
- Viral Oncogenesis Section in State Key Laboratory for Diagnosis & Treatment of Infectious Diseases, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, P. R. China
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Kelemen O, Convertini P, Zhang Z, Wen Y, Shen M, Falaleeva M, Stamm S. Function of alternative splicing. Gene 2013; 514:1-30. [PMID: 22909801 PMCID: PMC5632952 DOI: 10.1016/j.gene.2012.07.083] [Citation(s) in RCA: 548] [Impact Index Per Article: 45.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2012] [Revised: 07/21/2012] [Accepted: 07/30/2012] [Indexed: 12/15/2022]
Abstract
Almost all polymerase II transcripts undergo alternative pre-mRNA splicing. Here, we review the functions of alternative splicing events that have been experimentally determined. The overall function of alternative splicing is to increase the diversity of mRNAs expressed from the genome. Alternative splicing changes proteins encoded by mRNAs, which has profound functional effects. Experimental analysis of these protein isoforms showed that alternative splicing regulates binding between proteins, between proteins and nucleic acids as well as between proteins and membranes. Alternative splicing regulates the localization of proteins, their enzymatic properties and their interaction with ligands. In most cases, changes caused by individual splicing isoforms are small. However, cells typically coordinate numerous changes in 'splicing programs', which can have strong effects on cell proliferation, cell survival and properties of the nervous system. Due to its widespread usage and molecular versatility, alternative splicing emerges as a central element in gene regulation that interferes with almost every biological function analyzed.
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Affiliation(s)
- Olga Kelemen
- Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky, United States of America
| | - Paolo Convertini
- Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky, United States of America
| | - Zhaiyi Zhang
- Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky, United States of America
| | - Yuan Wen
- Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky, United States of America
| | - Manli Shen
- Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky, United States of America
| | - Marina Falaleeva
- Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky, United States of America
| | - Stefan Stamm
- Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky, United States of America
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Abstract
INTRODUCTION Since its discovery nearly 20 years ago, the Ron receptor tyrosine kinase has been extensively studied. These studies have elucidated many of the major signaling pathways activated by Ron. In the context of the inflammation and cancer, studies have shown that Ron plays differential roles; Ron activation limits the inflammatory response, whereas in cancer, Ron activation is associated with increased metastases and poor prognosis. AREAS COVERED This review discusses the current literature with regard to Ron signaling and consequences of its activation in cancer as well as its role in cancer therapy. Further, we discuss the mechanisms by which Ron influences the inflammatory response and its role in chronic inflammatory diseases. Finally, we discuss Ron's connection between chronic inflammation and progression to cancer. EXPERT OPINION The complex nature of Ron's signaling paradigm necessitates additional studies to understand the pathways by which Ron is functioning and how these differ in inflammation and cancer. This will be vital to understanding the impact that Ron signaling has in disease states. Additional studies of targeted therapies, either alone or in conjunction with current therapies are needed to determine if inhibition of Ron signaling will provide long-term benefits to cancer patients.
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Affiliation(s)
- Nancy M Benight
- University of Cincinnati College of Medicine, Cincinnati Veterans Affairs Medical Center, Department of Cancer and Cell Biology, OH 45267-0521, USA
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Sharda DR, Yu S, Ray M, Squadrito ML, De Palma M, Wynn TA, Morris SM, Hankey PA. Regulation of macrophage arginase expression and tumor growth by the Ron receptor tyrosine kinase. THE JOURNAL OF IMMUNOLOGY 2011; 187:2181-92. [PMID: 21810604 DOI: 10.4049/jimmunol.1003460] [Citation(s) in RCA: 108] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
M1 activation of macrophages promotes inflammation and immunity to intracellular pathogens, whereas M2 macrophage activation promotes resolution of inflammation, wound healing, and tumor growth. These divergent phenotypes are characterized, in part, by the expression of inducible NO synthase and arginase I (Arg1) in M1 versus M2 activated macrophages, respectively. In this study, we demonstrate that the Ron receptor tyrosine kinase tips the balance of macrophage activation by attenuating the M1 phenotype while promoting expression of Arg1 through a Stat6-independent mechanism. Induction of the Arg1 promoter by Ron is mediated by an AP-1 site located 433 bp upstream of the transcription start site. Treatment of primary macrophages with macrophage stimulating protein, the ligand for Ron, induces potent MAPK activation, upregulates Fos, and enhances binding of Fos to the AP-1 site in the Arg1 promoter. In vivo, Arg1 expression in tumor-associated macrophages (TAMs) from Ron(-/-) mice was significantly reduced compared with that in TAMs from control animals. Furthermore, we show that Ron is expressed specifically by Tie2-expressing macrophages, a TAM subset that exhibits a markedly skewed M2 and protumoral phenotype. Decreased Arg1 in TAMs from Ron(-/-) mice was associated with reduced syngeneic tumor growth in these animals. These findings indicate that Ron induces Arg1 expression in macrophages through a previously uncharacterized AP-1 site in the Arg1 promoter and that Ron could be therapeutically targeted in the tumor microenvironment to inhibit tumor growth by targeting expression of Arg1.
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Affiliation(s)
- Daniel R Sharda
- Graduate Program in Pathobiology, Department of Veterinary and Biomedical Sciences, Pennsylvania State University, University Park, PA 16802, USA
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Ray M, Yu S, Sharda DR, Wilson CB, Liu Q, Kaushal N, Prabhu KS, Hankey PA. Inhibition of TLR4-induced IκB kinase activity by the RON receptor tyrosine kinase and its ligand, macrophage-stimulating protein. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2010; 185:7309-16. [PMID: 21078906 PMCID: PMC4815273 DOI: 10.4049/jimmunol.1000095] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
The RON receptor tyrosine kinase regulates the balance between classical (M1) and alternative (M2) macrophage activation. In primary macrophages, the ligand for Ron, macrophage-stimulating protein (MSP), inhibits the expression of inducible NO synthase, a marker of classically activated macrophages, whereas promoting the expression of arginase I, a marker of alternative activation. Ron(-/-) mice express increased levels of IL-12, a product of classically activated macrophages, after endotoxin administration, resulting in increased serum IFN-γ levels and enhanced susceptibility to septic shock. In this study, we demonstrate that MSP inhibits LPS-induced IL-12p40 expression, and this inhibition is dependent on the docking site tyrosines in Ron. To further define this inhibition, we examined the effect of Ron on signaling pathways downstream of Ron. We found that MSP does not inhibit the MyD88-independent activation of IFN regulatory factor 3 and production of IFN-β in response to LPS, nor does it inhibit MyD88-dependent TGF-β-activated kinase phosphorylation or MAPK activation in primary macrophages. However, the induction of IκB kinase activity, IκB degradation, and DNA binding of NF-κB after LPS stimulation is delayed in the presence of MSP. In addition, Ron inhibits serine phosphorylation of p65 and NF-κB transcriptional activity induced by LPS stimulation of TLR4. Finally, MSP inhibits the NF-κB-dependent upregulation of the nuclear IκB family member, IκBζ, a positive regulator of secondary response genes including IL-12p40. LPS also induces expression of Ron and an N-terminally truncated form of Ron, Sf-Ron, in primary macrophages, suggesting that the upregulation of Ron by LPS could provide classical feedback regulation of TLR signaling.
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Affiliation(s)
- Manujendra Ray
- Department of Veterinary and Biomedical Science, The Pennsylvania State University, University Park, PA 16802
- Graduate Program in Immunology and Infectious Disease, The Pennsylvania State University, University Park, PA 16802
| | - Shan Yu
- Department of Veterinary and Biomedical Science, The Pennsylvania State University, University Park, PA 16802
- Graduate Program in Physiology, The Pennsylvania State University, University Park, PA 16802
| | - Daniel R. Sharda
- Department of Veterinary and Biomedical Science, The Pennsylvania State University, University Park, PA 16802
- Graduate Program in Pathobiology, The Pennsylvania State University, University Park, PA 16802
| | - Caleph B. Wilson
- Department of Veterinary and Biomedical Science, The Pennsylvania State University, University Park, PA 16802
- Graduate Program in Pathobiology, The Pennsylvania State University, University Park, PA 16802
| | - QingPing Liu
- Department of Veterinary and Biomedical Science, The Pennsylvania State University, University Park, PA 16802
| | - Naveen Kaushal
- Department of Veterinary and Biomedical Science, The Pennsylvania State University, University Park, PA 16802
| | - K. Sandeep Prabhu
- Department of Veterinary and Biomedical Science, The Pennsylvania State University, University Park, PA 16802
- Graduate Program in Immunology and Infectious Disease, The Pennsylvania State University, University Park, PA 16802
- Graduate Program in Pathobiology, The Pennsylvania State University, University Park, PA 16802
| | - Pamela A. Hankey
- Department of Veterinary and Biomedical Science, The Pennsylvania State University, University Park, PA 16802
- Graduate Program in Immunology and Infectious Disease, The Pennsylvania State University, University Park, PA 16802
- Graduate Program in Physiology, The Pennsylvania State University, University Park, PA 16802
- Graduate Program in Pathobiology, The Pennsylvania State University, University Park, PA 16802
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Lu Y, Yao HP, Wang MH. Significance of the entire C-terminus in biological activities mediated by the RON receptor tyrosine kinase and its oncogenic variant RON160. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2008; 27:55. [PMID: 18950514 PMCID: PMC2584002 DOI: 10.1186/1756-9966-27-55] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/10/2008] [Accepted: 10/25/2008] [Indexed: 01/28/2023]
Abstract
The RON receptor tyrosine kinase regulates epithelial cell homeostasis and tumorigenesis by transducing multiple signals through its functional domains. The present study was to determine the significance of the entire C-terminus in RON or its variant RON160-mediated activities related to cell motility and tumorigenesis. Analysis of protein phosphorylation revealed that elimination of the entire C-terminus significantly impairs the ligand-dependent or independent RON or RON160 phosphorylation and dimerization. Phosphorylation of downstream signaling proteins such as Erk1/2, AKT, and p38 MAP kinase was also diminished in cells expressing the C-terminus-free RON or RON160. These dysfunctional activities were accompanied with the inability of truncated RON or RON160 to mediate cytoplasmic β-catenin accumulation. Functional analysis further demonstrated that truncation of the C-terminus significantly impairs RON or RON160-mediated cell proliferation, morphological changes, and cellular migration. Significantly, oncogenic RON160-mediated tumor growth in athymic nude mice was lost after the deletion of the C-terminus. Thus, the C-terminus is a critical component of the RON receptor. The entire C-terminus is required for RON or RON160-mediated intracellular signaling events leading to various cellular activities.
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Affiliation(s)
- Yi Lu
- Laboratory of Cancer Biology and Therapeutics, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, PR China.
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Kalantari P, Harandi OF, Hankey PA, Henderson AJ. HIV-1 Tat mediates degradation of RON receptor tyrosine kinase, a regulator of inflammation. THE JOURNAL OF IMMUNOLOGY 2008; 181:1548-55. [PMID: 18606710 DOI: 10.4049/jimmunol.181.2.1548] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
HIV encodes several proteins, including Tat, that have been demonstrated to modulate the expression of receptors critical for innate immunity, including MHC class I, mannose receptor, and beta(2)-microglobulin. We demonstrate that Tat targets the receptor tyrosine kinase recepteur d'origine nantais (RON), which negatively regulates inflammation and HIV transcription, for proteosome degradation. Tat decreases cell surface RON expression in HIV-infected monocytic cells, and Tat-mediated degradation of RON protein is blocked by inhibitors of proteosome activity. Tat specifically induced down-regulation of RON and not other cell surface receptors, such as the transferrin receptor, the receptor tyrosine kinase TrkA, or monocytic markers CD14 and ICAM-1. The Tat trans activation domain is required for RON degradation, and this down-regulation is dependent on the integrity of the kinase domain of RON receptor. We propose that Tat mediates degradation of RON through a ubiquitin-proteosome pathway, and suggest that by targeting signals that modulate inflammation, Tat creates a microenvironment that is optimal for HIV replication and progression of AIDS-associated diseases.
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Affiliation(s)
- Parisa Kalantari
- Graduate Program in Pathobiology, Center for Molecular Immunology and Infectious Diseases, Pennsylvania State University, PA 16802, USA
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Wagh PK, Peace BE, Waltz SE. Met-related receptor tyrosine kinase Ron in tumor growth and metastasis. Adv Cancer Res 2008; 100:1-33. [PMID: 18620091 DOI: 10.1016/s0065-230x(08)00001-8] [Citation(s) in RCA: 127] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
The Ron receptor is a member of the Met family of cell surface receptor tyrosine kinases and is primarily expressed on epithelial cells and macrophages. The biological response of Ron is mediated by binding of its ligand, hepatocyte growth factor-like protein/macrophage stimulating-protein (HGFL). HGFL is primarily synthesized and secreted from hepatocytes as an inactive precursor and is activated at the cell surface. Binding of HGFL to Ron activates Ron and leads to the induction of a variety of intracellular signaling cascades that leads to cellular growth, motility and invasion. Recent studies have documented Ron overexpression in a variety of human cancers including breast, colon, liver, pancreas, and bladder. Moreover, clinical studies have also shown that Ron overexpression is associated with both worse patient outcomes as well as metastasis. Forced overexpression of Ron in transgenic mice leads to tumorigenesis in both the lung and the mammary gland and is associated with metastatic dissemination. While Ron overexpression appears to be a hallmark of many human cancers, the mechanisms by which Ron induces tumorigenesis and metastasis are still unclear. Several strategies are currently being undertaken to inhibit Ron as a potential therapeutic target; current strategies include the use of Ron blocking proteins, small interfering RNA (siRNA), monoclonal antibodies, and small molecule inhibitors. In total, these data suggest that Ron is a critical factor in tumorigenesis and that inhibition of this protein, alone or in combination with current therapies, may prove beneficial in the treatment of cancer patients.
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Affiliation(s)
- Purnima K Wagh
- Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0558, USA
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Klatt A, Zhang Z, Kalantari P, Hankey PA, Gilmour DS, Henderson AJ. The receptor tyrosine kinase RON represses HIV-1 transcription by targeting RNA polymerase II processivity. THE JOURNAL OF IMMUNOLOGY 2008; 180:1670-7. [PMID: 18209063 DOI: 10.4049/jimmunol.180.3.1670] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Efficient HIV-1 transcription requires the induction of cellular transcription factors, such as NF-kappaB, and the viral factor Tat, which through the recruitment of P-TEFb enhances processive transcription. However, whether cellular signals repress HIV-1 transcription to establish proviral latency has not been well studied. Previously, it has been shown that the receptor tyrosine kinase RON inhibits HIV transcription. To gain insights into the biochemical mechanisms by which RON inhibits transcription we examined the binding of transcription factors to the HIV provirus long terminal repeat using chromatin immunoprecipitation. RON expression decreased basal levels of NF-kappaB and RNA polymerase II (Pol II) binding to the HIV provirus long terminal repeat but did not prevent the induction of these complexes following treatment with cytokines. However, RON did decrease efficient transcription elongation because reduced RNA Pol II was associated with HIV-1 genomic sequences downstream of the transcriptional start site. There was a correlation between RON expression and increased binding of factors that negatively regulate transcription elongation, NELF, Spt5, and Pcf11. Furthermore, the ability of RON to inhibit HIV-1 transcription was sensitive to a histone deacetylase inhibitor and was associated with nucleosome remodeling. These results indicate that RON represses HIV transcription at multiple transcriptional check points including initiation, elongation and chromatin organization and are the first studies to show that cellular signaling pathways target Pol II pausing to repress gene expression.
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Affiliation(s)
- Alicia Klatt
- Center of Molecular Immunology and Infectious Diseases, Department of Veterinary and Biomedical Sciences, Pennsylvania State University, University Park, PA 16802, USA
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Angeloni D, Danilkovitch-Miagkova A, Ivanova T, Braga E, Zabarovsky E, Lerman MI. Hypermethylation of Ron proximal promoter associates with lack of full-length Ron and transcription of oncogenic short-Ron from an internal promoter. Oncogene 2007; 26:4499-512. [PMID: 17297469 DOI: 10.1038/sj.onc.1210238] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The gene for tyrosine-kinase receptor Ron (MST1R) resides in the chromosome 3p21.3 region, frequently affected in common human malignancies. The gene generates two transcripts, 5 and 2 kb-long, full-length Ron (flRon) and short-form Ron (sfRon), respectively. Here, we show for the first time that the variegated Ron expression is associated with variations in the methylation patterns of two distinct CpG islands in Ron proximal promoter. Widespread hypermethylation associates with lack of flRon whereas hypermethylation of the distal island associates with transcription of sfRon, a constitutively active tyrosine-kinase that drives cell proliferation. sfRon inhibition with kinase-dead transgenes decreases cancer cell growth and induces cellular differentiation. sfRon could be a new drug target in cancer types in which it contributes to tumor progression.
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Affiliation(s)
- D Angeloni
- Laboratory of Immunobiology, Center for Cancer Research, National Cancer Institute, Frederick, MD, USA.
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Correll PH, Paulson RF, Wei X. Molecular regulation of receptor tyrosine kinases in hematopoietic malignancies. Gene 2006; 374:26-38. [PMID: 16524673 DOI: 10.1016/j.gene.2006.01.023] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2005] [Revised: 01/02/2006] [Accepted: 01/08/2006] [Indexed: 10/24/2022]
Abstract
Dysregulation of receptor tyrosine kinase (RTK) activity has been implicated in the progression of a variety of human leukemias. Most notably, mutations and chromosomal translocations affecting regulation of tyrosine kinase activity in the Kit receptor, the Flt3 receptor, and the PDGFbeta/FGF1 receptors have been demonstrated in mast cell leukemia, acute myeloid leukemia (AML), and chronic myelogenous leukemias (CML), respectively. In addition, critical but non-overlapping roles for the Ron and Kit receptor tyrosine kinases in the progression of animal models of erythroleukemia have been demonstrated [Persons, D., Paulson, R., Loyd, M., Herley, M., Bodner, S., Bernstein, A., Correll, P. and Ney, P., 1999. Fv2 encodes a truncated form of the Stk receptor tyrosine kinase. Nat. Gen. 23, 159-165.; Subramanian, A., Teal, H.E., Correll, P.H. and Paulson, R.F., 2005. Resistance to friend virus-induced erythroleukemia in W/Wv mice is caused by a spleen-specific defect which results in a severe reduction in target cells and a lack of Sf-Stk expression. J. Virol. 79 (23), 14586-14594.]. The various classes of RTKs implicated in the progression of leukemia have been recently reviewed [Reilly, J., 2003. Receptor tyrosine kinases in normal and malignant haematopoiesis. Blood Rev. 17 (4), 241-248.]. Here, we will discuss the mechanism by which alterations in these receptors result in transformation of hematopoietic cells, in the context of what is known about the molecular regulation of RTK activity, with a focus on our recent studies of the Ron receptor tyrosine kinase.
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Affiliation(s)
- Pamela H Correll
- Department of Veterinary and Biomedical Sciences, Center for Molecular Immunology and Infectious Disease, The Pennsylvania State University, 115 Henning Building, University Park, PA 16802-3500, United States.
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Germano S, Barberis D, Santoro MM, Penengo L, Citri A, Yarden Y, Gaudino G. Geldanamycins trigger a novel Ron degradative pathway, hampering oncogenic signaling. J Biol Chem 2006; 281:21710-21719. [PMID: 16740632 DOI: 10.1074/jbc.m602014200] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Ron, the tyrosine kinase receptor for macrophage-stimulating protein is responsible for proliferation and migration of cells from different tissues. Ron can acquire oncogenic potential by single point mutations in the kinase domain, and dysregulated Ron signaling has been involved in the development of different human cancers. We have previously shown that ligand-activated Ron recruits the negative regulator c-Cbl, which mediates its ubiquitylation and degradation. Here we report that Ron is ubiquitylated also by the U-box E3 ligase C-terminal Hsc70-interacting protein (CHIP), recruited via chaperone intermediates Hsp90 and Hsc70. Gene silencing shows that CHIP activity is necessary to mediate Ron degradation upon cell treatment with Hsp90 inhibitors geldanamycins. The oncogenic Ron(M1254T) receptor escapes from c-Cbl negative regulation but retains a strong association with CHIP. This constitutively active mutant of Ron displays increased sensitivity to geldanamycins, enhanced physical interaction with Hsp90, and more rapid degradation rate. Cell growth and migration, as well as the transforming potential evoked by Ron(M1254T), are abrogated upon Hsp90 inhibition. These data highlight a novel mechanism for Ron degradation and propose Hsp90 antagonists like geldanamycins as suitable pharmacological agents for therapy of cancers where altered Ron signaling is involved.
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Affiliation(s)
- Serena Germano
- Department DISCAFF and DFB Center, University of Piemonte Orientale "A. Avogadro," Novara 28100, Italy
| | - Davide Barberis
- Department DISCAFF and DFB Center, University of Piemonte Orientale "A. Avogadro," Novara 28100, Italy
| | - Massimo M Santoro
- Department DISCAFF and DFB Center, University of Piemonte Orientale "A. Avogadro," Novara 28100, Italy
| | - Lorenza Penengo
- Department DISCAFF and DFB Center, University of Piemonte Orientale "A. Avogadro," Novara 28100, Italy
| | - Ami Citri
- Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel
| | - Yosef Yarden
- Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel
| | - Giovanni Gaudino
- Department DISCAFF and DFB Center, University of Piemonte Orientale "A. Avogadro," Novara 28100, Italy.
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Varela M, Chow YH, Sturkie C, Murcia P, Palmarini M. Association of RON tyrosine kinase with the Jaagsiekte sheep retrovirus envelope glycoprotein. Virology 2006; 350:347-57. [PMID: 16500691 DOI: 10.1016/j.virol.2006.01.040] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2005] [Revised: 01/06/2006] [Accepted: 01/26/2006] [Indexed: 01/21/2023]
Abstract
The envelope (Env) of Jaagsiekte sheep retrovirus (JSRV) functions as an oncoprotein. One of the mechanisms of JSRV-induced cell transformation that has been proposed for epithelial cells involves JSRV Env binding Hyaluronidase 2 (the JSRV receptor), thereby inducing its degradation and allowing the release and activation of RON tyrosine kinase which is normally suppressed by HYAL-2. In this study, we report that HYAL-2 and RON are not critical for the JSRV Env-induced transformation of the rat epithelial cell line IEC-18, while the cytoplasmic tail of the JSRV Env is critical to transform this cell line. We have also determined that RON can associate with the JSRV Env under normal and stringent conditions. In addition, the cytoplasmic tail of the JSRV and the enJS5F16 (non oncogenic JSRV-related endogenous retrovirus) Env proteins appears to have a major influence on the activation status of RON. Thus, it appears that the interaction of the JSRV Env with RON is more complex than previously thought and requires further investigation.
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Affiliation(s)
- Mariana Varela
- Institute of Comparative Medicine, University of Glasgow Veterinary School, 464 Bearsden Road, Glasgow G61 1QH, UK
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