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

J Cell Biol. 2012 Apr 30;197(3):421-37. doi: 10.1083/jcb.201108143. Epub 2012 Apr 23.

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