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PMID: 22529104 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

Hic-5 promotes invadopodia formation and invasion during TGF-β-induced epithelial-mesenchymal transition.

The Journal of cell biology ·Vol. 197 ·No. 3 ·2012-04-30 ·Pages 421-37

Pignatelli J, Tumbarello DA, Schmidt RP, Turner CE

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.

MeSH Terms
Animals Blotting, Western Breast/metabolism,pathology Cell Adhesion Cell Movement/physiology Cell Surface Extensions/metabolism Cells, Cultured Cytoskeletal Proteins/antagonists & inhibitors,genetics,metabolism DNA-Binding Proteins/antagonists & inhibitors,genetics,metabolism Epithelial-Mesenchymal Transition Extracellular Matrix/metabolism Fluorescent Antibody Technique, Indirect Humans LIM Domain Proteins/antagonists & inhibitors,genetics,metabolism Mice Phosphorylation RNA, Small Interfering/genetics Signal Transduction Transforming Growth Factor beta/genetics,metabolism p38 Mitogen-Activated Protein Kinases/metabolism rhoA GTP-Binding Protein/antagonists & inhibitors,genetics,metabolism src-Family Kinases/metabolism
Chemicals
Cytoskeletal Proteins DNA-Binding Proteins LIM Domain Proteins RNA, Small Interfering Tgfb1i1 protein, mouse Transforming Growth Factor beta src-Family Kinases p38 Mitogen-Activated Protein Kinases rhoA GTP-Binding Protein
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Pignatelli Jeanine
Department of Cell and Developmental Biology, State University of New York Upstate Medical University, Syracuse, NY 13210, USA.
Tumbarello David A
Schmidt Ronald P
Turner Christopher E
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Article Info
Journal
The Journal of cell biology
Abbr.
J Cell Biol
ISSN
1540-8140
DOI
10.1083/jcb.201108143
Published
2012-04-30
Epub
2012-00-23
Pages
421-37
Language
English
Region
United States
NLM ID
0375356
PMCID
PMC3341156
Subset
IM
Grants
NHLBI NIH HHS · R01 HL070244 · United States
NIGMS NIH HHS · R01GM47607 · United States
NCI NIH HHS · R01 CA163296 · United States
NIGMS NIH HHS · R01 GM047607 · United States
NHLBI NIH HHS · R01HL070244 · United States
External Links
PubMed source DOI: 10.1083/jcb.201108143 PMC Full Text View journal details
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