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Crosstalk between Fibroblast Growth Factor (FGF) Receptor and Integrin through Direct Integrin Binding to FGF and Resulting Integrin-FGF-FGFR Ternary Complex Formation  [PDF]
Seiji Mori,Yoshikazu Takada
Medical Sciences , 2013, DOI: 10.3390/medsci1010020
Abstract: Fibroblast growth factors (FGFs) play a critical role in diverse physiological processes and the pathogenesis of diseases. Integrins are involved in FGF signaling, since integrin antagonists suppress FGF signaling. This is called integrin-FGF crosstalk, while the specifics of the crosstalk are unclear. This review highlights recent findings that FGF1 directly interacts with integrin αvβ3, and the resulting integrin-FGF-fibroblast growth factor receptor (FGFR) ternary complex formation is essential for FGF1-induced cell proliferation, migration and angiogenesis. An integrin-binding defective FGF1 mutant (Arg-50 to Glu, R50E) is defective in ternary complex formation and in inducing cell proliferation, migration and angiogenesis, while R50E still binds to the FGF receptor and heparin. In addition, R50E suppressed tumorigenesis in vivo, while wild-type (WT) FGF1 enhanced it. Thus, the direct interaction between FGF1 and integrin αvβ3 is a potential therapeutic target, and R50E is a potential therapeutic agent.
The linkage between β1 integrin and the actin cytoskeleton is differentially regulated by tyrosine and serine/threonine phosphorylation of β1 integrin in normal and cancerous human breast cells
Kazuhide Takahashi
BMC Cell Biology , 2001, DOI: 10.1186/1471-2121-2-23
Abstract: The β1 integrin immunoprecipitates from either HBE or MCF-7 cells involved α-actinin while actin coprecipitated with β1 integrin from HBE cells but not from MCF-7 cells. Immunoblotting using the anti-phosphotyrosine (PY) antibody indicated the phosphorylation of β1 integrin at least at tyrosine in both cells. Dephosphorylation of β1 integrin from HBE cells by protein tyrosine phosphatase (PTP), but not by protein serine/threonine phosphatase (PP), caused dissociation of actin from β1 integrin, although dephosphorylation of it from MCF-7 cells by either PTP or PP caused association of the two proteins. In MCF-7 cells β1 integrin coprecipitated doublet of proteins having the Ca2+/calmodulin-dependent protein kinase (CaMK) II activity that was susceptible to KN-62, a specific inhibitor of CaMKII.The results suggest that β1 integrin is tyrosine phosphorylated and links with actin via α-actinin in HBE cells but prevented from linking with actin in MCF-7 cells by phosphorylation at both tyrosine and serine/threonine of β1 integrin which forms a complex with α-actinin and CaMKII. Thus the linkage formation of β1 integrin with actin may be differentially regulated by its tyrosine and serine/threonine phosphorylation in normal HBE cells and breast cancer MCF-7 cells.The integrin family of surface receptors play a critical role in many cellular processes that include cell adhesion, cell spreading, and growth signaling [1-6]. Integrins interact extracellularly with the substratum such as collagens at specific sites called focal adhesions and intracellularly with many actin-binding proteins such as α-actinin, talin, and vinculin, thereby linking these proteins with the actin cytoskeleton. Links between cell surface receptor β integrins and the actin cytoskeleton are though to be established in more than one way. Integrin binds to talin [7], which also binds to vinculin [8-10], which in turn binds to α-actinin [11,12], which then binds to actin. This constitutes a three-protein
Crosstalk between EGFR and integrin affects invasion and proliferation of gastric cancer cell line, SGC7901
Dan L,Jian D,Na L,Xiaozhong W
OncoTargets and Therapy , 2012,
Abstract: Li Dan,1,* Ding Jian,2,* Lin Na,1 Wang Xiaozhong,1 1Digestive Department, the Union Hospital of Fujian Medical University, Fujian, People’s Republic of China; 2Digestive Department, the First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, People’s Republic of China*These authors contributed equally to this workBackground/objective: To investigate the crosstalk between epidermal growth factor receptor (EGFR) and integrin-mediated signal transduction pathways in human gastric adenocarcinoma cells.Methods: EGF was used as a ligand of EGFR to stimulate the gastric adenocarcinoma cell, SGC7901. Signal molecules downstream of the integrin, FAK(Y397) and p130cas(Y410) phosphorylation, were measured by immunoprecipitation and western blot. Fibronectin (Fn) was used as a ligand of integrin to stimulate the same cell line. Signal molecules downstream of EGFR and extracellular signal-regulated kinase (ERK) general phosphorylation were also measured. Focal adhesion kinase (FAK) small-interfering RNA was designed and transfected into SGC7901 cells to decrease the expression of FAK. Modified Boyden chambers and MTT assay were used to examine the effect of FAK inhibition on the invasiveness and proliferation of SGC7901.Results: EGF activated FAK(Y397) and p130cas(Y410) phosphorylation, while Fn activated ERK general phosphorylation. Inhibition of FAK expression decreased p130cas(Y410) phosphorylation activated by EGF and ERK general phosphorylation activated by Fn, also decreased the invasiveness and proliferation of SGC7901 cells activated by EGF or Fn.Conclusion: There is crosstalk between EGFR and integrin signal transduction. FAK may be a key cross point of the two signal pathways and acts as a potential target for human gastric cancer therapy.Keywords: gastric adenocarcinoma, epidermal growth factor receptor, integrin, focal adhesion kinase, crosstalk
Phosphatase of regenerating liver-3 directly interacts with integrin β1 and regulates its phosphorylation at tyrosine 783  [cached]
Tian Wei,Qu Like,Meng Lin,Liu Caiyun
BMC Biochemistry , 2012, DOI: 10.1186/1471-2091-13-22
Abstract: Background Phosphatase of regenerating liver-3 (PRL-3 or PTP4A3) has been implicated in controlling cancer cell proliferation, motility, metastasis, and angiogenesis. Deregulated expression of PRL-3 is highly correlated with cancer progression and predicts poor survival. Although PRL-3 was categorized as a tyrosine phosphatase, its cellular substrates remain largely unknown. Results We demonstrated that PRL-3 interacts with integrin β1 in cancer cells. Recombinant PRL-3 associates with the intracellular domain of integrin β1 in vitro. Silencing of integrin α1 enhances PRL-3-integrin β1 interaction. Furthermore, PRL-3 diminishes tyrosine phosphorylation of integrin β1 in vitro and in vivo. With site-specific anti-phosphotyrosine antibodies against residues in the intracellular domain of integrin β1, tyrosine-783, but not tyrosine-795, is shown to be dephosphorylated by PRL-3 in a catalytic activity-dependant manner. Phosphorylation of Y783 is potentiated by ablation of PRL-3 or by treatment with a chemical inhibitor of PRL-3. Conversely, depletion of integrin α1 decreases the phosphorylation of this site. Conclusions Our results revealed a direct interaction between PRL-3 and integrin β1 and characterized Y783 of integrin β1 as a bona fide substrate of PRL-3, which is negatively regulated by integrin α1.
Integrin-Mediated Actions of Thyroid Hormone Analogues on Tumor Cell Chemosensitivity, Integrin-Growth Factor Receptor Crosstalk and Inflammatory Gene Expression  [cached]
Aleck H. Hercbergs,Faith B. Davis,Hung-Yun Lin,Mary K. Luidens
Cancer and Clinical Oncology , 2012, DOI: 10.5539/cco.v1n1p32
Abstract: Tetraiodothyroacetic acid (tetrac) and its nanoparticulate formulation induce apoptosis in cancer cells, oppose angiogenesis about xenografted human tumors and block cancer cell repair of double-stranded DNA breaks. These nongenomic actions of tetrac are initiated at a tetrac-thyroid hormone receptor on plasma membrane integrin avb3. In this review, we examine additional anti-cancer activities of tetrac formulations at avb3 and what is known about their mechanisms. These activities include 1) reversal of cancer cell chemoresistance (= induction of chemosensitization) and 2) disruption of crosstalk between avb3 and nearby cell surface growth factor receptors. In addition, nanoparticulate tetrac 3) alters expression of differentially-regulated inflammation-relevant genes that may be important to inflammation-supported cancer. For example, the agent downregulates genes whose products mediate cytokine responses and upregulates suppressor of cytokine signaling, SOCS4. Such actions of tetrac formulations define a multi-target functional profile, although the activities of tetrac begin at a single anatomic plasma membrane receptor on integrin avb3.
Integrin and GPCR Crosstalk in the Regulation of ASM Contraction Signaling in Asthma  [PDF]
Chun Ming Teoh,John Kit Chung Tam,Thai Tran
Journal of Allergy , 2012, DOI: 10.1155/2012/341282
Abstract: Airway hyperresponsiveness (AHR) is one of the cardinal features of asthma. Contraction of airway smooth muscle (ASM) cells that line the airway wall is thought to influence aspects of AHR, resulting in excessive narrowing or occlusion of the airway. ASM contraction is primarily controlled by agonists that bind G protein-coupled receptor (GPCR), which are expressed on ASM. Integrins also play a role in regulating ASM contraction signaling. As therapies for asthma are based on symptom relief, better understanding of the crosstalk between GPCRs and integrins holds good promise for the design of more effective therapies that target the underlying cellular and molecular mechanism that governs AHR. In this paper, we will review current knowledge about integrins and GPCRs in their regulation of ASM contraction signaling and discuss the emerging concept of crosstalk between the two and the implication of this crosstalk on the development of agents that target AHR. 1. Introduction Airway hyperresponsiveness (AHR) is the exaggerated response to relatively low concentrations of constricting agents (such as methacholine or histamine) or indirectly acting stimuli (such as cold air, respiratory infections or allergens, exercise, or cigarette smoke) that is observed in asthmatic subjects [1]. Contraction of airway smooth muscle (ASM) cells that line the airway wall is thought to influence aspects of AHR, culminating in the generation of force and excessive narrowing or occlusion of the airway [2]. ASM contraction is primarily controlled by agonists that bind G protein-coupled receptors (GPCR), which are expressed on ASM. Studies have shown that the asthmatic airways can be completely occluded even with only 40% contraction of ASM cells following an asthma exacerbation to GPCR agonists, such as histamine, that induce muscle shortening [3, 4]. Therefore, ASM GPCRs are important targets for therapeutic agents in asthma treatment. However, there is increasing evidence to suggest that chronic use of -adrenergic receptor agonists, which act on GPCRs, is associated with worsening of bronchoconstrictor response to airway spasmogen [5], loss of asthma control, and exacerbation of asthma symptoms [6, 7], as well as an increased incidence of asthma-related morbidity and mortality [8]. Moreover, glucocorticoids, which are used as first line therapy for the treatment of inflammation associated with asthma, decrease AHR only if introduced early in disease diagnosis [9, 10]. Even then, there are side effects associated with the use of glucocorticoid when used at high dose and over
Crosstalk between EGFR and integrin affects invasion and proliferation of gastric cancer cell line, SGC7901
Dan L, Jian D, Na L, Xiaozhong W
OncoTargets and Therapy , 2012, DOI: http://dx.doi.org/10.2147/OTT.S35322
Abstract: osstalk between EGFR and integrin affects invasion and proliferation of gastric cancer cell line, SGC7901 Original Research (1584) Total Article Views Authors: Dan L, Jian D, Na L, Xiaozhong W Published Date October 2012 Volume 2012:5 Pages 271 - 277 DOI: http://dx.doi.org/10.2147/OTT.S35322 Received: 24 June 2012 Accepted: 13 August 2012 Published: 23 October 2012 Li Dan,1,* Ding Jian,2,* Lin Na,1 Wang Xiaozhong,1 1Digestive Department, the Union Hospital of Fujian Medical University, Fujian, People’s Republic of China; 2Digestive Department, the First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, People’s Republic of China *These authors contributed equally to this work Background/objective: To investigate the crosstalk between epidermal growth factor receptor (EGFR) and integrin-mediated signal transduction pathways in human gastric adenocarcinoma cells. Methods: EGF was used as a ligand of EGFR to stimulate the gastric adenocarcinoma cell, SGC7901. Signal molecules downstream of the integrin, FAK(Y397) and p130cas(Y410) phosphorylation, were measured by immunoprecipitation and western blot. Fibronectin (Fn) was used as a ligand of integrin to stimulate the same cell line. Signal molecules downstream of EGFR and extracellular signal-regulated kinase (ERK) general phosphorylation were also measured. Focal adhesion kinase (FAK) small-interfering RNA was designed and transfected into SGC7901 cells to decrease the expression of FAK. Modified Boyden chambers and MTT assay were used to examine the effect of FAK inhibition on the invasiveness and proliferation of SGC7901. Results: EGF activated FAK(Y397) and p130cas(Y410) phosphorylation, while Fn activated ERK general phosphorylation. Inhibition of FAK expression decreased p130cas(Y410) phosphorylation activated by EGF and ERK general phosphorylation activated by Fn, also decreased the invasiveness and proliferation of SGC7901 cells activated by EGF or Fn. Conclusion: There is crosstalk between EGFR and integrin signal transduction. FAK may be a key cross point of the two signal pathways and acts as a potential target for human gastric cancer therapy.
Phospho-Tyrosine(s) vs. Phosphatidylinositol Binding in Shc Mediated Integrin Signaling  [PDF]
Xiaochen Lin, Olga Vinogradova
American Journal of Molecular Biology (AJMB) , 2015, DOI: 10.4236/ajmb.2015.52003
Abstract: The Shc adaptor protein, particularly its p52 isoform, has been identified as a primary signaling partner for the tyrosine(s)-phosphorylated cytoplasmic tails of activated β3 integrins. Inspired by our recent structure of the Shc PTB domain in complex with a bi-phosphorylated peptide derived from β3 cytoplasmic tail, we have initiated the investigation of Shc interaction with phospholipids of the membrane. We are particularly focused on PtdIns and their effects on Shc mediated integrin signaling in vitro. Here we present thermodynamic profiles and molecular details of the interactions between Shc, integrin, and PtdIns, all of which have been studied by ITC and solution NMR methods. A model of p52 Shc interaction with phosphorylated β3 integrin cytoplasmic tail at the cytosolic face of the plasma membrane is proposed based on these data.
Notch, IL-1 and Leptin Crosstalk Outcome (NILCO) Is Critical for Leptin-Induced Proliferation, Migration and VEGF/VEGFR-2 Expression in Breast Cancer  [PDF]
Shanchun Guo, Ruben R. Gonzalez-Perez
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0021467
Abstract: High levels of pro-angiogenic factors, leptin, IL-1, Notch and VEGF (ligands and receptors), are found in breast cancer, which is commonly correlated with metastasis and lower survival of patients. We have previously reported that leptin induces the growth of breast cancer and the expression of VEGF/VEGFR-2 and IL-1 system. We hypothesized that Notch, IL-1 and leptin crosstalk outcome (NILCO) plays an essential role in the regulation of leptin-mediated induction of proliferation/migration and expression of pro-angiogenic molecules in breast cancer. To test this hypothesis, leptin's effects on the expression and activation of Notch signaling pathway and VEGF/VEGFR-2/IL-1 were determined in mouse (4T1, EMT6 and MMT) breast cancer cells. Remarkably, leptin up-regulated Notch1-4/JAG1/Dll-4, Notch target genes: Hey2 and survivin, together with IL-1 and VEGF/VEGFR-2. RNA knockdown and pharmacological inhibitors of leptin signaling significantly abrogated activity of reporter gene-luciferase CSL (RBP-Jk) promoter, showing that it was linked to leptin-activated JAK2/STAT3, MAPK, PI-3K/mTOR, p38 and JNK signaling pathways. Interestingly, leptin upregulatory effects on cell proliferation/migration and pro-angiogenic factors Notch, IL-1 and VEGF/VEGFR-2 were abrogated by a γ-secretase inhibitor, DAPT, as well as siRNA against CSL. In addition, blockade of IL-1R tI inhibited leptin-induced Notch, Hey2 and survivin as well as VEGF/VEGFR-2 expression. These data suggest leptin is an inducer of Notch (expression/activation) and IL-1 signaling modulates leptin effects on Notch and VEGF/VEGFR-2. We show for the first time that a novel unveiled crosstalk between Notch, IL-1 and leptin (NILCO) occurs in breast cancer. Leptin induction of proliferation/migration and upregulation of VEGF/VEGFR-2 in breast cancer cells were related to an intact Notch signaling axis. NILCO could represent the integration of developmental, pro-inflammatory and pro-angiogenic signals critical for leptin-induced cell proliferation/migration and regulation of VEGF/VEGFR-2 in breast cancer. Targeting NILCO might help to design new pharmacological strategies aimed at controlling breast cancer growth and angiogenesis.
The Immune Adaptor ADAP Regulates Reciprocal TGF-β1-Integrin Crosstalk to Protect from Influenza Virus Infection  [PDF]
Chunyang Li?,Shaozhuo Jiao?,Guojun Wang?,Yunzhen Gao?,Chang Liu?,Xijun He?,Chi Zhang?,Jun Xiao?,Weiyun Li?,Guoquan Zhang
PLOS Pathogens , 2015, DOI: 10.1371/journal.ppat.1004824
Abstract: Highly pathogenic avian influenza virus (HPAI, such as H5N1) infection causes severe cytokine storm and fatal respiratory immunopathogenesis in human and animal. Although TGF-β1 and the integrin CD103 in CD8+ T cells play protective roles in H5N1 virus infection, it is not fully understood which key signaling proteins control the TGF-β1-integrin crosstalk in CD8+ T cells to protect from H5N1 virus infection. This study showed that ADAP (Adhesion and Degranulation-promoting Adapter Protein) formed a complex with TRAF6 and TAK1 in CD8+ T cells, and activated SMAD3 to increase autocrine TGF-β1 production. Further, TGF-β1 induced CD103 expression via an ADAP-, TRAF6- and SMAD3-dependent manner. In response to influenza virus infection (i.e. H5N1 or H1N1), lung infiltrating ADAP-/- CD8+ T cells significantly reduced the expression levels of TGF-β1, CD103 and VLA-1. ADAP-/- mice as well as Rag1-/- mice receiving ADAP-/- T cells enhanced mortality with significant higher levels of inflammatory cytokines and chemokines in lungs. Together, we have demonstrated that ADAP regulates the positive feedback loop of TGF-β1 production and TGF-β1-induced CD103 expression in CD8+ T cells via the TβRI-TRAF6-TAK1-SMAD3 pathway and protects from influenza virus infection. It is critical to further explore whether the SNP polymorphisms located in human ADAP gene are associated with disease susceptibility in response to influenza virus infection.
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