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.
Publication types
-
Research Support, N.I.H., Extramural
MeSH terms
-
Animals
-
Blotting, Western
-
Breast / metabolism*
-
Breast / pathology*
-
Cell Adhesion
-
Cell Movement / physiology*
-
Cell Surface Extensions / metabolism*
-
Cells, Cultured
-
Cytoskeletal Proteins / antagonists & inhibitors
-
Cytoskeletal Proteins / genetics
-
Cytoskeletal Proteins / metabolism*
-
DNA-Binding Proteins / antagonists & inhibitors
-
DNA-Binding Proteins / genetics
-
DNA-Binding Proteins / metabolism*
-
Epithelial-Mesenchymal Transition*
-
Extracellular Matrix / metabolism
-
Fluorescent Antibody Technique, Indirect
-
Humans
-
LIM Domain Proteins / antagonists & inhibitors
-
LIM Domain Proteins / genetics
-
LIM Domain Proteins / metabolism*
-
Mice
-
Phosphorylation
-
RNA, Small Interfering / genetics
-
Signal Transduction
-
Transforming Growth Factor beta / genetics
-
Transforming Growth Factor beta / metabolism*
-
p38 Mitogen-Activated Protein Kinases / metabolism
-
rhoA GTP-Binding Protein / antagonists & inhibitors
-
rhoA GTP-Binding Protein / genetics
-
rhoA GTP-Binding Protein / metabolism
-
src-Family Kinases / metabolism
Substances
-
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