Induction of cell retraction by the combined actions of Abl-CrkII and Rho-ROCK1 signaling

J Cell Biol. 2008 Nov 17;183(4):711-23. doi: 10.1083/jcb.200801192. Epub 2008 Nov 10.

Abstract

Dynamic modulation of cell adhesion is integral to a wide range of biological processes. The small guanosine triphosphatase (GTPase) Rap1 is an important regulator of cell-cell and cell-matrix adhesions. We show here that induced expression of activated Abl tyrosine kinase reduces Rap1-GTP levels through phosphorylation of Tyr221 of CrkII, which disrupts interaction of CrkII with C3G, a guanine nucleotide exchange factor for Rap1. Abl-dependent down-regulation of Rap1-GTP causes cell rounding and detachment only when the Rho-ROCK1 pathway is also activated, for example, by lysophosphatidic acid (LPA). During ephrin-A1-induced retraction of PC3 prostate cancer cells, we show that endogenous Abl is activated and disrupts the CrkII-C3G complex to reduce Rap1-GTP. Interestingly, ephrin-A1-induced PC3 cell retraction also requires LPA, which stimulates Rho to a much higher level than that is activated by ephrin-A1. Our results establish Rap1 as another downstream target of the Abl-CrkII signaling module and show that Abl-CrkII collaborates with Rho-ROCK1 to stimulate cell retraction.

Publication types

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

MeSH terms

  • Cell Line, Tumor
  • Ephrin-A1 / genetics
  • Ephrin-A1 / metabolism
  • Guanine Nucleotide-Releasing Factor 2 / genetics
  • Guanine Nucleotide-Releasing Factor 2 / metabolism
  • Humans
  • Lysophospholipids / genetics
  • Lysophospholipids / metabolism
  • Male
  • Proto-Oncogene Proteins c-abl / genetics
  • Proto-Oncogene Proteins c-abl / metabolism*
  • Proto-Oncogene Proteins c-crk / genetics
  • Proto-Oncogene Proteins c-crk / metabolism*
  • Signal Transduction / physiology*
  • rap1 GTP-Binding Proteins / genetics
  • rap1 GTP-Binding Proteins / metabolism*
  • rho-Associated Kinases / genetics
  • rho-Associated Kinases / metabolism*

Substances

  • Ephrin-A1
  • Guanine Nucleotide-Releasing Factor 2
  • Lysophospholipids
  • Proto-Oncogene Proteins c-crk
  • Proto-Oncogene Proteins c-abl
  • ROCK1 protein, human
  • rho-Associated Kinases
  • rap1 GTP-Binding Proteins
  • lysophosphatidic acid