Role of c-Abl tyrosine kinase in smooth muscle cell migration

Am J Physiol Cell Physiol. 2014 Apr 15;306(8):C753-61. doi: 10.1152/ajpcell.00327.2013. Epub 2014 Jan 29.

Abstract

c-Abl is a nonreceptor protein tyrosine kinase that has a role in regulating smooth muscle cell proliferation and contraction. The role of c-Abl in smooth muscle cell migration has not been investigated. In the present study, c-Abl was found in the leading edge of smooth muscle cells. Knockdown of c-Abl by RNA interference attenuated smooth muscle cell motility as evidenced by time-lapse microscopy. Furthermore, the actin-associated proteins cortactin and profilin-1 (Pfn-1) have been implicated in cell migration. In this study, cell adhesion induced cortactin phosphorylation at Tyr-421, an indication of cortactin activation. Phospho-cortactin and Pfn-1 were also found in the cell edge. Pfn-1 directly interacted with cortactin in vitro. Silencing of c-Abl attenuated adhesion-induced cortactin phosphorylation and Pfn-1 localization in the cell edge. To assess the role of cortactin/Pfn-1 coupling, we developed a cell-permeable peptide. Treatment with the peptide inhibited the interaction of cortactin with Pfn-1 without affecting cortactin phosphorylation. Moreover, treatment with the peptide impaired the recruitment of Pfn-1 to the leading edge and cell migration. Finally, β1-integrin was required for the recruitment of c-Abl to the cell edge. Inhibition of actin dynamics impaired the spatial distribution of c-Abl. These results suggest that β1-integrin may recruit c-Abl to the leading cell edge, which may regulate cortactin phosphorylation in response to cell adhesion. Phosphorylated cortactin may facilitate the recruitment of Pfn-1 to the cell edge, which promotes localized actin polymerization, leading edge formation, and cell movement. Conversely, actin dynamics may strengthen the recruitment of c-Abl to the leading edge.

Keywords: actin cytoskeleton; adapter protein; cell migration; smooth muscle; tyrosine kinase.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Blotting, Far-Western
  • Cell Adhesion
  • Cell Movement / physiology*
  • Cells, Cultured
  • Cortactin / genetics
  • Cortactin / metabolism
  • Gene Expression Regulation, Enzymologic
  • Humans
  • Integrin beta1 / genetics
  • Integrin beta1 / metabolism
  • Myocytes, Smooth Muscle / enzymology*
  • Myocytes, Smooth Muscle / physiology*
  • Phosphorylation
  • Profilins / genetics
  • Profilins / metabolism
  • Proto-Oncogene Proteins c-abl / genetics
  • Proto-Oncogene Proteins c-abl / metabolism*
  • RNA Interference
  • Transduction, Genetic

Substances

  • CTTN protein, human
  • Cortactin
  • Integrin beta1
  • PFN1 protein, human
  • Profilins
  • Proto-Oncogene Proteins c-abl