• cortactin
• cytoskeleton
• pathogenesis
• signaling
• virulence

• Cortactin/metabolism
• Humans
• Host-Pathogen Interactions
• Animals
• Fungi/metabolism
• Fungi/pathogenicity
• Viruses/metabolism
• Viruses/pathogenicity
• Signal Transduction
• Phosphorylation
• Virus Diseases/metabolism

• BA 1671/16-1 Deutsche Forschungsgemeinschaft
• TE 776/3-1 Deutsche Forschungsgemeinschaft

• TGFβ/RhoA
• apico–basal polarity
• polybasic domains
• septin 9

• Cortactin
• Cytoskeleton
• Pathogenesis
• Signaling
• Virulence

• lung injury
• acute respiratory distress syndrome
• ards
• cortactin
• nmmlck
• non-muscle myosin light chain kinase
• health disparities
• endothelial barrier
• pulmonary endothelium
• vascular leak
• lung vasculature
• lung inflammation
• ventilator induced lung injury
• vili

• AHCC®
• KLM1-R
• cortactin
• migration
• pancreatic cancer

The scaffolding protein family Fe65, composed of Fe65, Fe65L1, and Fe65L2, was identified as an interaction partner of the amyloid precursor protein (APP), which plays a key function in Alzheimer’s disease. All three Fe65 family members possess three highly conserved interaction domains, forming complexes with diverse binding partners that can be assigned to different cellular functions, such as transactivation of genes in the nucleus, modulation of calcium homeostasis and lipid metabolism, and regulation of the actin cytoskeleton. In this article, we rule out putative new intracellular signaling mechanisms of the APP-interacting protein Fe65 in the regulation of actin cytoskeleton dynamics in the context of various neuronal functions, such as cell migration, neurite outgrowth, and synaptic plasticity.

• Arf6
• Arp2/3
• DOCK
• ELMO
• Mena
• Rac
• Tip60
• cortactin
• neurite outgrowth
• structural synaptic plasticity

• Actin Cytoskeleton/metabolism
• Actins/metabolism
• Amyloid beta-Protein Precursor/metabolism
• Animals
• Humans
• Models, Biological
• Nerve Tissue Proteins/genetics
• Nerve Tissue Proteins/metabolism
• Protein Binding

• CX3CL1
• cancer
• cortactin
• invasion
• lung

• Animals
• Apoptosis
• CX3C Chemokine Receptor 1/metabolism
• Cell Line, Tumor
• Cell Movement
• Cell Proliferation
• Chemokine CXCL1/metabolism
• Cortactin/metabolism
• Humans
• Lung Neoplasms/metabolism
• Lung Neoplasms/pathology
• Male
• Mice, Nude
• Neoplasm Invasiveness
• Phosphorylation
• Phosphotyrosine/metabolism
• Proto-Oncogene Proteins c-abl/metabolism
• Signal Transduction/drug effects
• src-Family Kinases/metabolism
• Mice

• CYS19207 Chongqing Municipal Education Commission
• NSFC81672103 to QS National Natural Science Foundation of China
• Chongqing Municipal Education Commission
• National Natural Science Foundation of China

• Actin
• Cancer
• Cytoskeleton
• Formins
• MicroRNAs
• Signaling
• WASp family

Src is the prototypal member of Src Family tyrosine Kinases (SFKs), a large non-receptor kinase class that controls multiple signaling pathways in animal cells. SFKs activation is necessary for the mitogenic signal from many growth factors, but also for the acquisition of migratory and invasive phenotype. Indeed, oncogenic activation of SFKs has been demonstrated to play an important role in solid cancers; promoting tumor growth and formation of distant metastases. Several drugs targeting SFKs have been developed and tested in preclinical models and many of them have successfully reached clinical use in hematologic cancers. Although in solid tumors SFKs inhibitors have consistently confirmed their ability in blocking cancer cell progression in several experimental models; their utilization in clinical trials has unveiled unexpected complications against an effective utilization in patients. In this review, we summarize basic molecular mechanisms involving SFKs in cancer spreading and metastasization; and discuss preclinical and clinical data highlighting the main challenges for their future application as therapeutic targets in solid cancer progression

• Src
• cancer invasion
• cancer metastasization
• cancer migration
• clinical trial
• dasatinib
• epithelial-to-mesenchymal transition
• src family tyrosine kinases
• targeted therapy

• Abl
• CagA
• FAK
• Helicobacter pylori
• SHP2
• Src
• T4SS
• cagPAI
• signaling
• type IV secretion
• tyrosine kinases

• TE776/3 1 Deutsche Forschungsgemeinschaft

• Breast cancer
• Metastasis
• RHO signalling

• R01 CA236361 NCI NIH HHS
• Breast Cancer Research Foundation (BCRF)

Optic nerve head (ONH) astrocytes provide support for axons, but exhibit structural and functional changes (termed reactivity) in a number of glaucoma models. The purpose of this study was to determine if ONH astrocyte structural reactivity is axon-dependent.

Using rats, we combine retrobulbar optic nerve transection (ONT) with acute controlled elevation of intraocular pressure (CEI), to induce total optic nerve axon loss and ONH astrocyte reactivity, respectively. Animals were euthanized immediately or 1 day post CEI, in the presence or absence of ONT. ONH sections were labeled with fluorescent-tagged phalloidin and antibodies against β3 tubulin, phosphorylated cortactin, phosphorylated paxillin, or complement C3. ONH label intensities were quantified after confocal microscopy. Retrobulbar nerves were assessed for axon injury by light microscopy.

While ONT alone had no effect on ONH astrocyte structural orientation, astrocytes demonstrated significant reorganization of cellular extensions within hours after CEI, even when combined with ONT. However, ONH astrocytes displayed differential intensities of actin (phosphorylated cortactin) and focal adhesion (phosphorylated paxillin) mediators in response to CEI alone, ONT alone, or the combination of CEI and ONT. Lastly, label intensities of complement C3 within the ONH were unchanged in eyes subjected to CEI alone, ONT alone, or the combination of CEI and ONT, relative to controls.

Early ONH astrocyte structural reactivity to elevated IOP is multifaceted, displaying both axon dependent and independent responses. These findings have important implications for pursuing astrocytes as diagnostic and therapeutic targets in neurodegenerative disorders with fluctuating levels of axon injury.

• Cortactin
• cutaneous squamous cell carcinoma
• molecular biomarker
• oncogenic effect
• phosphorylation

• Cortactin
• Pancreatic ductal adenocarcinoma
• Tumor cell migration and invasion

• Medizinische Fakultät, Westfälische Wilhelms-Universität Münster
• Deutsche Forschungsgemeinschaft

Licorice is an herb extensively used for both culinary and medicinal purposes. Various constituents of licorice have been shown to exhibit anti-tumorigenic effect in diverse cancer types. However, majority of these studies focus on the aspect of their growth-suppressive role. In this study, we systematically analyzed known licorice’s constituents on the goal of identifying component(s) that can effectively suppress both cell migration and growth.

Effect of licorice’s constituents on cell growth was evaluated by MTT assay while cell migration was assessed by both wound-healing and Transwell assays. Cytoskeleton reorganization and focal adhesion assembly were visualized by immunofluorescence staining with labeled phalloidin and anti-paxillin antibody. Activity of Src in cells was judged by western blot using phosphor-Src416 antibody while Src kinase activity was measured using Promega Src kinase assay system. Anti-tumorigenic capabilities of isoliquiritigenin (ISL) and 2, 4, 2′, 4’-Tetrahydroxychalcone (THC) were investigated using lung cancer xenograft model.

Using a panel of lung cancer cell lines, ISL was identified as the only licorice’s constituent capable of inhibiting both cell migration and growth. ISL-led inhibition in cell migration resulted from impaired cytoskeleton reorganization and focal adhesion assembly. Assessing the phosphorylation of 141 cytoskeleton dynamics-associated proteins revealed that ISL reduced the abundance of Tyr421-phosphorylation of cortactin, Tyr925- and Tyr861-phosphorylation of FAK, indicating the involvement of Src because these sites are known to be phosphorylated by Src. Enigmatically, ISL inhibited Src in cells while displayed no effect on Src activity in cell-free system. The discrepancy was explained by the observation that THC, one of the major ISL metabolite identified in lung cancer cells abrogated Src activity both in cells and cell-free system. Similar to ISL, THC deterred cell migration and abolished cytoskeleton reorganization/focal adhesion assembly. Furthermore, we showed both ISL and THC suppressed in vitro lung cancer cell invasion and in vivo tumor progression.

Our study suggests that ISL inhibits lung cancer cell migration and tumorigenesis by interfering with Src through its metabolite THC. As licorice is safely used for culinary purposes, our study suggests that ISL or THC may be safely used as a Src inhibitor.

The online version of this article (10.1186/s13046-018-0902-4) contains supplementary material, which is available to authorized users.

• Cell migration
• Isoliquitigenin
• Lung cancer
• Metabolite
• Src

• 11q13
• CTTN
• carcinogenesis
• cortactin
• oral cancer

• ovarian cancer
• phosphoproteomics
• spleen tyrosine kinase
• cell invasion
• f-actin dynamics

• Basement Membrane/drug effects
• Basement Membrane/metabolism
• Cell Line, Tumor
• Cell Movement/drug effects
• Humans
• Neoplasm Invasiveness/pathology
• Phosphorylation/drug effects
• Signal Transduction/drug effects
• Syk Kinase/metabolism

• U01 CA200469 NCI NIH HHS
• R21 CA187512 NCI NIH HHS
• R01 CA148826 NCI NIH HHS
• K01 CA166576 NCI NIH HHS
• K22 CA212060 NCI NIH HHS
• R01 CA215483 NCI NIH HHS
• R01 CA174388 NCI NIH HHS

• ARP2/3
• Cortactin
• Rac1
• Rho GTPases
• actin cytoskeleton
• invadopodia
• invasion
• migration
• podosome

• downregulation
• endosomes
• endothelium
• guanine nucleotide exchange factors
• signal transduction
• vascular endothelial growth factor receptor-2

Upon cell stimulation, the network of cortical actin filaments is rearranged to facilitate the neurosecretory process. This actin rearrangement includes both disruption of the preexisting actin network and de novo actin polymerization. However, the mechanism by which a Ca²⁺ signal elicits the formation of new actin filaments remains uncertain. Cortactin, an actin-binding protein that promotes actin polymerization in synergy with the nucleation promoting factor N-WASP, could play a key role in this mechanism. We addressed this hypothesis by analyzing de novo actin polymerization and exocytosis in bovine adrenal chromaffin cells expressing different cortactin or N-WASP domains, or cortactin mutants that fail to interact with proline-rich domain (PRD)-containing proteins, including N-WASP, or to be phosphorylated by Ca²⁺-dependent kinases, such as ERK1/2 and Src. Our results show that the activation of nicotinic receptors in chromaffin cells promotes cortactin translocation to the cell cortex, where it colocalizes with actin filaments. We further found that, in association with PRD-containing proteins, cortactin contributes to the Ca²⁺-dependent formation of F-actin, and regulates fusion pore dynamics and the number of exocytotic events induced by activation of nicotinic receptors. However, whereas the actions of cortactin on the fusion pore dynamics seems to depend on the availability of monomeric actin and its phosphorylation by ERK1/2 and Src kinases, cortactin regulates the extent of exocytosis by a mechanism independent of actin polymerization. Together our findings point out a role for cortactin as a critical modulator of actin filament formation and exocytosis in neuroendocrine cells.

• N-WASP
• actin polymerization
• catecholamines
• chromaffin cells
• cortactin
• exocytosis
• fusion pore
• neuroendocrine cells

• AMP-activated protein kinases
• atherosclerosis
• caveolin-1
• cortactin
• nitric oxide synthase type III

• cell invasion
• cell migration
• cell motility
• cellular regulation
• microtubule
• microtubule-associated protein (MAP)

• Actin-Related Protein 2-3 Complex/metabolism
• Actins/metabolism
• Biological Transport
• Cell Line, Tumor
• Cell Membrane/metabolism
• Cortactin/metabolism
• Cortactin/ultrastructure
• Exosomes/metabolism
• Exosomes/ultrastructure
• Humans
• Microfilament Proteins
• Models, Biological
• Molecular Docking Simulation
• Multivesicular Bodies/metabolism
• Multivesicular Bodies/ultrastructure
• Phenotype
• Protein Binding
• Pseudopodia/metabolism
• RNA, Small Interfering/metabolism
• Tetraspanin 30/metabolism
• rab GTP-Binding Proteins/metabolism

• UL1 TR000445 NCATS NIH HHS
• R01 CA163592 NCI NIH HHS
• R01 DK095811 NIDDK NIH HHS
• P30 DK058404 NIDDK NIH HHS
• P30 HD015052 NICHD NIH HHS
• R01 DK075555 NIDDK NIH HHS
• P30 EY008126 NEI NIH HHS
• P30 DK020593 NIDDK NIH HHS
• P30 CA068485 NCI NIH HHS
• UL1 RR024975 NCRR NIH HHS
• U24 DK059637 NIDDK NIH HHS
• National Institutes of Health
• Vanderbilt University
• American Cancer Society
• American Heart Association
• Ministry of Education, Culture, Sports, Science, and Technology

Monocyte chemotactic protein 1 (MCP1) stimulates phosphorylation of cortactin on Y421 and Y446 residues in a time-dependent manner and phosphorylation at Y446 but not Y421 residue is required for MCP1-induced CDK-interacting protein 1 (p21Cip1) nuclear export and degradation in facilitating human aortic smooth muscle cell (HASMC) proliferation. In addition, MCP1-induced cortactin tyrosine phosphorylation, p21Cip1 degradation and HASMC proliferation are dependent on Fyn activation. Upstream to Fyn, MCP1 stimulated C-C chemokine receptor type 2 (CCR2) and Gi/o and inhibition of either one of these molecules using their specific antagonists or inhibitors attenuated MCP1-induced cortactin tyrosine phosphorylation, p21Cip1 degradation and HASMC proliferation. Cortactin phosphorylation at Y446 residue is also required for another G protein-coupled receptor (GPCR) agonist, thrombin-induced p21Cip1 nuclear export and its degradation in promoting HASMC proliferation. Quite interestingly, the receptor tyrosine kinase (RTK) agonist, platelet-derived growth factor-BB (PDGF-BB)-induced p21Cip1 degradation and HASMC proliferation do not require cortactin tyrosine phosphorylation. Together, these findings demonstrate that tyrosine phosphorylation of cortactin at Y446 residue is selective for only GPCR but not RTK agonist-induced nuclear export and proteolytic degradation of p21Cip1 in HASMC proliferation.

Integrins, a family of heterodimeric adhesion receptors are implicated in cell migration, development and cancer progression. They can adopt conformations that reflect their activation states and thereby impact adhesion strength and migration. Integrins in an intermediate activation state may be optimal for migration and we have shown previously that fully activated integrin α9β1 corresponds with less migratory behaviour in melanoma cells. Here, we aimed to identify components associated with the activation status of α9β1. Using cancer cell lines with naturally occuring high levels of this integrin, activation by α9β1-specific ligands led to upregulation of fibronectin matrix assembly and tyrosine phosphorylation of cortactin on tyrosine 470 (Y470). Specifically, cortactin phosphorylated on Y470, but not Y421, redistributed together with α9β1 to focal adhesions where active β1 integrin also localises, upon integrin activation. This was commensurate with reduced migration. The localisation and phosphorylation of cortactin Y470 was regulated by Yes kinase and PTEN phosphatase. Cortactin levels influenced fibronectin matrix assembly and active β1 integrin on the cell surface, being inversely correlated with migratory behaviour. This study underlines the complex interplay between cortactin and α9β1 integrin that regulates cell-extracellular matrix interactions.

• Breast cancer
• CD44s
• Invadopodia
• Metastasis
• Splice isoform

• acute lung injury
• cortactin
• endothelial wound healing
• wound healing assay

• Acute Lung Injury/genetics
• Acute Lung Injury/metabolism
• Acute Lung Injury/pathology
• Animals
• Blood-Air Barrier/metabolism
• Blood-Air Barrier/pathology
• Cattle
• Cells, Cultured
• Cortactin/genetics
• Cortactin/metabolism
• Endothelial Cells/metabolism
• Endothelial Cells/pathology
• Humans
• Lysophospholipids/metabolism
• Polymorphism, Single Nucleotide
• Pseudopodia/genetics
• Pseudopodia/metabolism
• Sphingosine/analogs & derivatives
• Sphingosine/metabolism
• Wound Healing

• P01 HL-58064 NHLBI NIH HHS
• R01 HL-88144 NHLBI NIH HHS
• R01 GM097443 NIGMS NIH HHS
• R56 HL088144 NHLBI NIH HHS
• 5R01 GM-097443 NIGMS NIH HHS
• P01 HL126609 NHLBI NIH HHS
• P01 HL058064 NHLBI NIH HHS
• R01 HL091889 NHLBI NIH HHS

• Cell invasion
• Cortactin
• JAK2 kinase
• Prolactin
• Src kinase
• Tyrosine kinase

How Src tyrosine kinase and cortactin control actin organization and dynamics in neuronal growth cones is not well understood. Using multiple high-resolution imaging techniques, this study shows that Src and cortactin control the persistence of lamellipodial protrusion as well as the formation, stability, and elongation of filopodia in growth cones.

Src tyrosine kinases have been implicated in axonal growth and guidance; however, the underlying cellular mechanisms are not well understood. Specifically, it is unclear which aspects of actin organization and dynamics are regulated by Src in neuronal growth cones. Here, we investigated the function of Src2 and one of its substrates, cortactin, in lamellipodia and filopodia of Aplysia growth cones. We found that up-regulation of Src2 activation state or cortactin increased lamellipodial length, protrusion time, and actin network density, whereas down-regulation had opposite effects. Furthermore, Src2 or cortactin up-regulation increased filopodial density, length, and protrusion time, whereas down-regulation promoted lateral movements of filopodia. Fluorescent speckle microscopy revealed that rates of actin assembly and retrograde flow were not affected in either case. In summary, our results support a model in which Src and cortactin regulate growth cone motility by increasing actin network density and protrusion persistence of lamellipodia by controlling the state of actin-driven protrusion versus retraction. In addition, both proteins promote the formation and stability of actin bundles in filopodia.

The mechanism by which the hippocampus facilitates declarative memory formation appears to involve, among other things, restructuring of the actin cytoskeleton within neuronal dendrites. One protein involved in this process is cortactin, which is an important link between extracellular signaling and cytoskeletal reorganization. In this paper, we demonstrate that total hippocampal cortactin, as well as Y421-phosphorylated cortactin are transiently reduced following spatial working memory formation in the radial arm maze (RAM). Because cortactin is a substrate of the cysteine protease calpain, we also assessed the effect of chronic calpain inhibition on RAM performance and cortactin expression. Calpain inhibition impaired spatial working memory and blocked the reduction in hippocampal cortactin levels following RAM training. These findings add to a growing body of research implicating cortactin and calpain in hippocampus-dependent memory formation.

• calpain
• cortactin
• hippocampus
• radial arm maze
• spatial working memory

• U54 GM104942 NIGMS NIH HHS

• ADAM Proteins/metabolism
• Animals
• Cell Surface Extensions/metabolism
• Cytoskeleton/metabolism
• Epithelial-Mesenchymal Transition
• Extracellular Matrix/metabolism
• Humans
• Matrix Metalloproteinase 14/metabolism
• Neoplasm Invasiveness
• Neoplasm Metastasis
• Neoplasms/metabolism
• Neoplasms/pathology
• Signal Transduction

• R01 CA168689 NCI NIH HHS
• 1DP2OD002420 NIH HHS
• 1R01CA168689 NCI NIH HHS
• DP2 OD002420 NIH HHS
• 5K12GM068524 NIGMS NIH HHS
• T32 GM007752 NIGMS NIH HHS
• K12 GM068524 NIGMS NIH HHS
• 5T32GM007752 NIGMS NIH HHS

• Antineoplastic Agents/pharmacology
• Apoptosis/drug effects
• Benzamides/pharmacology
• Cell Cycle/drug effects
• Cell Line, Tumor
• Cell Proliferation/drug effects
• Forkhead Box Protein O3
• Forkhead Transcription Factors/metabolism
• Gene Expression
• Humans
• Lung Neoplasms/genetics
• Lung Neoplasms/metabolism
• Models, Biological
• Naphthols/pharmacology
• Proto-Oncogene Proteins c-akt/metabolism
• Signal Transduction/drug effects
• Tumor Stem Cell Assay
• beta Catenin/metabolism

• Actin
• Crystal Structure
• Phosphotyrosine
• Src Homology 2 Domain (SH2 Domain)
• Tyrosine-Protein Kinase (Tyrosine Kinase)

• Binding Sites/genetics
• Blotting, Western
• Cell Line, Tumor
• Cell Movement
• Cortactin/genetics
• Cortactin/metabolism
• Extracellular Signal-Regulated MAP Kinases/antagonists & inhibitors
• Extracellular Signal-Regulated MAP Kinases/metabolism
• F-Box Proteins/genetics
• F-Box Proteins/metabolism
• Flavonoids/pharmacology
• Humans
• Mutation
• Phosphorylation
• Proteasome Endopeptidase Complex/metabolism
• Protein Binding
• Protein Kinase Inhibitors/pharmacology
• Proteolysis/drug effects
• RNA Interference
• Serine/genetics
• Serine/metabolism
• Stomach Neoplasms/genetics
• Stomach Neoplasms/metabolism
• Stomach Neoplasms/pathology
• Ubiquitin-Protein Ligase Complexes
• Ubiquitin-Protein Ligases/genetics
• Ubiquitin-Protein Ligases/metabolism
• Ubiquitination

• Arp2/3
• CD4+ T cells
• HIV-1
• LIMK
• actin cytoskeleton
• cofilin
• macrophages

AIM: To study the effects of cortactin on the tumor biology of SGC-7901 cells and identify the mechanism involved in the process.

METHODS: Cell lines in which cortactin was stably overexpressed or knocked down as well as the respective control cell lines were established by standard molecular methods. The effects of cortactin on the proliferation, migration and invasion capacity of SGC-7901 cells were assessed by the MTT assay, colony formation, flow cytometry, transwell migration and matrigel invasion. Nude mouse models were also used to assess the role of cortactin in the growth and metastasis of SGC-7901 cells in vivo. Western blotting analysis was performed to detect the expression of epidermal growth factor receptor (EGFR) and downstream molecules.

RESULTS: Cell lines in which cortactin was stably overexpressed or knocked down as well as control cell lines were successfully established and designated as LV5-cortactin-SGC, LV5-SGC, LV3-shRNA-SGC and LV3-SGC. Cortactin overexpression promoted SGC-7901 cell migration (340.7 ±12.6 vs 229.1 ± 23.2, P < 0.01) and invasion (71.6 ± 5.2 vs 48.4 ± 3.6, P < 0.01). Cortactin downregulation impaired SGC-7901 cell migration (136.2 ± 19.8 vs 225 ± 17) and invasion (29.2 ± 5.2 vs 49.6 ± 3.8, P < 0.01). The results from the MTT and colony formation assays results indicated increased LV5-cortactin-SGC cell proliferation and decreased LV3-shRNA-SGC cell proliferation compared to the control cells. Flow cytometry analysis demonstrated that cortactin overexpression promoted the proliferation index of SGC-7901 cells, and the results were reversed when cortactin was downregulated. Mouse tumor models confirmed that cortactin expression increased SGC-7901 cell proliferation and metastasis in vivo. Western blotting analysis revealed that cortactin elevated EGFR expression and activated the downstream molecules.

CONCLUSION: Cortactin expression promoted the migration, invasion and proliferation of SGC-7901 cells both in vivo and in vitro. The EGFR signaling pathway is mechanistically involved.

• Gastric cancer
• Cortactin
• Epidermal growth factor receptor
• Invasion
• Metastasis
• Proliferation

• Animals
• Blotting, Western
• Cell Line, Tumor
• Cell Movement
• Cell Proliferation
• Cortactin/metabolism
• ErbB Receptors/metabolism
• Female
• Flow Cytometry
• Gene Expression Regulation, Neoplastic
• Humans
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Neoplasm Invasiveness
• Neoplasm Metastasis
• Phenotype
• Stomach Neoplasms/metabolism

Cortactin (CTTN), first identified as a major substrate of the Src tyrosine kinase, actively participates in branching F-actin assembly and in cell motility and invasion. CTTN gene is amplified and its protein is overexpressed in several types of cancer. The phosphorylated form of cortactin (pTyr⁴²¹) is required for cancer cell motility and invasion. In this study, we demonstrate that a majority of the tested primary colorectal tumor specimens show greatly enhanced expression of pTyr⁴²¹-CTTN, but no change at the mRNA level as compared to healthy subjects, thus suggesting post-translational activation rather than gene amplification in these tumors. Curcumin (diferulolylmethane), a natural compound with promising chemopreventive and chemosensitizing effects, reduced the indirect association of cortactin with the plasma membrane protein fraction in colon adenocarcinoma cells as measured by surface biotinylation, mass spectrometry, and Western blotting. Curcumin significantly decreased the pTyr⁴²¹-CTTN in HCT116 cells and SW480 cells, but was ineffective in HT-29 cells. Curcumin physically interacted with PTPN1 tyrosine phosphatases to increase its activity and lead to dephosphorylation of pTyr⁴²¹-CTTN. PTPN1 inhibition eliminated the effects of curcumin on pTyr⁴²¹-CTTN. Transduction with adenovirally-encoded CTTN increased migration of HCT116, SW480, and HT-29. Curcumin decreased migration of HCT116 and SW480 cells which highly express PTPN1, but not of HT-29 cells with significantly reduced endogenous expression of PTPN1. Curcumin significantly reduced the physical interaction of CTTN and pTyr⁴²¹-CTTN with p120 catenin (CTNND1). Collectively, these data suggest that curcumin is an activator of PTPN1 and can reduce cell motility in colon cancer via dephosphorylation of pTyr⁴²¹-CTTN which could be exploited for novel therapeutic approaches in colon cancer therapy based on tumor pTyr⁴²¹-CTTN expression.

• Adenocarcinoma/genetics
• Adenocarcinoma/metabolism
• Adenocarcinoma/pathology
• Antineoplastic Agents/metabolism
• Antineoplastic Agents/pharmacology
• Blotting, Western
• Catenins/metabolism
• Cell Line, Tumor
• Cell Membrane/metabolism
• Cell Movement/drug effects
• Colorectal Neoplasms/genetics
• Colorectal Neoplasms/metabolism
• Colorectal Neoplasms/pathology
• Cortactin/genetics
• Cortactin/metabolism
• Curcumin/metabolism
• Curcumin/pharmacology
• Gene Expression Regulation, Neoplastic/drug effects
• HCT116 Cells
• HT29 Cells
• Humans
• Immunohistochemistry
• Microscopy, Confocal
• Phosphorylation/drug effects
• Protein Binding/drug effects
• Protein Processing, Post-Translational/drug effects
• Protein Tyrosine Phosphatase, Non-Receptor Type 1/metabolism
• Reverse Transcriptase Polymerase Chain Reaction
• Tyrosine/metabolism
• Delta Catenin

• P30 CA023074 NCI NIH HHS
• P30 ES006694 NIEHS NIH HHS
• ES006694 NIEHS NIH HHS
• P30 CA 23074 NCI NIH HHS
• CA023074 NCI NIH HHS
• 5 R01 DK067286 NIDDK NIH HHS
• R01 DK067286 NIDDK NIH HHS

• abl
• imatinib mesylate
• invadopodia
• invasion
• head and neck cancer
• cortactin