title: Galectin-3- and phospho-caveolin-1-dependent outside-in integrin signaling mediates the EGF motogenic response in mammary cancer cells.
abstract: In murine mammary epithelial cancer cells, galectin-3 binding to β1,6-acetylglucosaminyltransferase V (Mgat5)-modified N-glycans restricts epidermal growth factor (EGF) receptor mobility in the plasma membrane and acts synergistically with phospho-caveolin-1 to promote integrin-dependent matrix remodeling and cell migration. We show that EGF signaling to RhoA is galectin-3 and phospho-caveolin-1 dependent and promotes the formation of transient, actin-rich, circular dorsal ruffles (CDRs), cell migration, and fibronectin fibrillogenesis via Src- and integrin-linked kinase (ILK)-dependent signaling. ILK, Src, and galectin-3 also mediate EGF stimulation of caveolin-1 phosphorylation. Direct activation of integrin with Mn2+ induces galectin-3, ILK, and Src-dependent RhoA activation and caveolin-1 phosphorylation. This suggests that in response to EGF, galectin-3 enables outside-in integrin signaling stimulating phospho-caveolin-1-dependent RhoA activation, actin reorganization in CDRs, cell migration, and fibronectin remodeling. Similarly, caveolin-1/galectin-3-dependent EGF signaling induces motility, peripheral actin ruffling, and RhoA activation in MDA-MB-231 human breast carcinoma cells, but not HeLa cells. These studies define a galectin-3/phospho-caveolin-1/RhoA signaling module that mediates integrin signaling downstream of growth factor activation, leading to actin and matrix remodeling and tumor cell migration in metastatic cancer cells.
authors: Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
authors: Cecile
authors: C
authors: Boscher
authors: Ivan R
authors: IR
authors: Nabi
mesh_terms: D000818:Animals; D001798:Blood Proteins; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051242:Caveolin 1 / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D005260:Female; D037502:Galectin 3 / Q000235:genetics / Q000378:metabolism*; D037161:Galectins; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016023:Integrins / Q000235:genetics / Q000378:metabolism; D008321:Mammary Glands, Animal / Q000378:metabolism / Q000473:pathology; D015674:Mammary Neoplasms, Animal / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D017351:N-Acetylglucosaminyltransferases / Q000172:deficiency / Q000235:genetics; D009928:Organ Specificity; D010766:Phosphorylation; D011134:Polysaccharides / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D020741:rho GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D020742:rhoA GTP-Binding Protein; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism; D000099200:Scaffold Protein ILK
chemical_list: D001798:Blood Proteins; D051242:Caveolin 1; D066246:ErbB Receptors; D037502:Galectin 3; D037161:Galectins; D016023:Integrins; D017351:N-Acetylglucosaminyltransferases; D011134:Polysaccharides; D017346:Protein Serine-Threonine Kinases; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein; D019061:src-Family Kinases; D000099200:Scaffold Protein ILK; C428445:LGALS3 protein, human; C485095:Lgals3 protein, mouse; C052254:alpha-1,6-mannosylglycoprotein beta 1,6-N-acetylglucosaminyltransferase; C526380:RhoA protein, mouse
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