title: Hic-5 promotes invadopodia formation and invasion during TGF-β-induced epithelial-mesenchymal transition.
abstract: Transforming growth factor β (TGF-β)-stimulated epithelial-mesenchymal transition (EMT) is an important developmental process that has also been implicated in increased cell invasion and metastatic potential of cancer cells. Expression of the focal adhesion protein Hic-5 has been shown to be up-regulated in epithelial cells in response to TGF-β. Herein, we demonstrate that TGF-β-induced Hic-5 up-regulation or ectopic expression of Hic-5 in normal MCF10A cells promoted increased extracellular matrix degradation and invasion through the formation of invadopodia. Hic-5 was tyrosine phosphorylated in an Src-dependent manner after TGF-β stimulation, and inhibition of Src activity or overexpression of a Y38/60F nonphosphorylatable mutant of Hic-5 inhibited matrix degradation and invasion. RhoC, but not RhoA, was also required for TGF-β- and Hic-5-induced matrix degradation. Hic-5 also induced matrix degradation, cell migration, and invasion in the absence of TGF-β via Rac1 regulation of p38 MAPK. These data identify Hic-5 as a critical mediator of TGF-β-stimulated invadopodia formation, cell migration, and invasion.
authors.affiliation: Department of Cell and Developmental Biology, State University of New York Upstate Medical University, Syracuse, NY 13210, USA.
authors.forename: Jeanine
authors.initials: J
authors.lastname: Pignatelli
authors.forename: David A
authors.initials: DA
authors.lastname: Tumbarello
authors.forename: Ronald P
authors.initials: RP
authors.lastname: Schmidt
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Turner
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001940:Breast / Q000378:metabolism* / Q000473:pathology*; D002448:Cell Adhesion; D002465:Cell Movement / Q000502:physiology*; D022081:Cell Surface Extensions / Q000378:metabolism*; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D058750:Epithelial-Mesenchymal Transition; D005109:Extracellular Matrix / Q000378:metabolism; D019084:Fluorescent Antibody Technique, Indirect; D006801:Humans; D060588:LIM Domain Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D060588:LIM Domain Proteins; D034741:RNA, Small Interfering; C090090:Tgfb1i1 protein, mouse; D016212:Transforming Growth Factor beta; D019061:src-Family Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020742:rhoA GTP-Binding Protein