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Departments of Pathology (S.-K.S., C.C.) and Anatomy and Cell Biology (C.N.), Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, Canada N6A 5C1
Address all correspondence and requests for reprints to: Dr. Chandan Chakraborty, Department of Pathology, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, Ontario, Canada N6A 5C1. E-mail: cchakrab{at}uwo.ca.
Both IGF-I and IGF-II stimulate migration of human extravillous trophoblast (EVT) cells. Although IGF-I is known to signal through IGF type 1 receptor (IGF1R), IGF-II 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 IGF-II on EVT cell migration. To distinguish IGF1R-dependent and -independent actions, we used picropodophyllin, a selective inhibitor of IGF1R tyrosine kinase, and IGF analogs with differential affinities for IGF1R, IGF-II/cation-independent mannose 6-phosphate receptor, and IGF-binding proteins. IGF1R-dependent actions of IGF-II were confirmed by showing the effects of IGF1R-selective agonist Des1–3 IGF-I. We used pharmacological inhibitors or selective small interfering RNAs to investigate the roles of RhoA, RhoC, Rac1, Cdc42, and Rho effector kinases called ROCK-I and -II in IGF-induced EVT cell migration. Although 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 IGF-II on EVT cell migration required ROCKs but not RhoA, RhoC, Rac1, or Cdc42. Most importantly, IGF1R-independent action of IGF-II was found to be exaggerated when RhoA or RhoC was down-regulated. Thus, different members of the Rho GTPase family regulate IGF-II-mediated EVT cell migration differentially, depending upon whether it signals through IGF1R or in an IGF1R-independent manner.
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  P. Fafet, C. Rebouissou, T. Maudelonde, and M.-L. Vignais Opposite Effects of Transforming Growth Factor-{beta} Activation and Rho-Associated Kinase Inhibition on Human Trophoblast Migration in a Reconstituted Placental-Endometrial Coculture System Endocrinology, September 1, 2008; 149(9): 4475 - 4485. [Abstract] [Full Text] [PDF]
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C. Nicola, A. Chirpac, P. K. Lala, and C. Chakraborty Roles of Rho Guanosine 5'-Triphosphatase A, Rho Kinases, and Extracellular Signal Regulated Kinase (1/2) in Prostaglandin E2-Mediated Migration of First-Trimester Human Extravillous Trophoblast Endocrinology, March 1, 2008; 149(3): 1243 - 1251. [Abstract] [Full Text] [PDF]
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