Induction of cell retraction by the combined actions of Abl-CrkII and Rho-ROCK1 signaling.
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.
Huang
XiaoDong
X
Division of Biological Sciences, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Wu
Diana
D
Jin
Hua
H
Stupack
Dwayne
D
Wang
Jean Y J
JY
D045744:Cell Line, Tumor; D036382:Ephrin-A1 / Q000235:genetics / Q000378:metabolism; D020735:Guanine Nucleotide-Releasing Factor 2 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008246:Lysophospholipids / Q000235:genetics / Q000378:metabolism; D008297:Male; D016315:Proto-Oncogene Proteins c-abl / Q000235:genetics / Q000378:metabolism*; D050737:Proto-Oncogene Proteins c-crk / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D020827:rap1 GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D054460:rho-Associated Kinases / Q000235:genetics / Q000378:metabolism*
D036382:Ephrin-A1; D020735:Guanine Nucleotide-Releasing Factor 2; D008246:Lysophospholipids; D050737:Proto-Oncogene Proteins c-crk; D016315:Proto-Oncogene Proteins c-abl; C515851:ROCK1 protein, human; D054460:rho-Associated Kinases; D020827:rap1 GTP-Binding Proteins; C032881:lysophosphatidic acid