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Submitted on April 13, 2007
Accepted on July 10, 2007
Departments of Pathology (S.-K.S, C.C.), and Anatomy and Cell Biology (C.N.), Schulich School of Medicine & Dentistry, The University of Western Ontario, London, Ontario, Ontario, Canada, N6A 5C1
* To whom correspondence should be addressed. E-mail: cchakrab{at}uwo.ca.
Both IGFI and IGFII stimulate migration of human extravillous trophoblast (EVT) cells. While IGFI is known to signal through IGF type I receptor (IGF1R), IGFII signals through IGF1R as well as in an IGF1R-independent manner. The purpose of this study was to investigate the roles of Rho GTPases in IGF1R-independent and -dependent actions of IGFII on EVT cell migration. To distinguish IGF1R-dependent and -independent actions, we used picropodophyllin (PPP), a selective inhibitor of IGF1R tyrosine kinase, and IGF analogs with differential affinities for IGF1R, IGFII/cation-independent mannose 6-phosphate receptor (IGFII/CI-M6PR) and IGFBPs. IGF1R-dependent actions of IGFII were confirmed by showing the effects of IGF1R-selective agonist Des (1-3) IGFI. We used pharmacological inhibitors or selective siRNAs to investigate the roles of RhoA, RhoC, Rac1, Cdc42 and Rho effector kinases called ROCK-I and -II in IGF-induced EVT cell migration. While basal migration of EVT cells required each member of the Rho GTPase family studied, IGF1R-dependent and -independent EVT cell migration exhibited differential requirements for these enzymes. IGF1R-mediated EVT cell migration was found to depend on RhoA and RhoC but not on Rac1 or Cdc42. However, IGF1R-independent effect of IGFII on EVT cell migration required ROCKs but not RhoA, RhoC, Rac1 or Cdc42. Most importantly, IGF1R-independent action of IGFII was found to be exaggerated when RhoA or RhoC was down-regulated. Thus, different members of the Rho GTPase family regulate IGFII-mediated EVT cell migration differentially, depending upon whether it signals through IGF1R or in an IGF1R-independent manner.
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