title: Rho guanosine 5'-triphosphatases differentially regulate insulin-like growth factor I (IGF-I) receptor-dependent and -independent actions of IGF-II on human trophoblast migration.
abstract: 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.
authors.affiliation: Department of Pathology, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, Ontario, Canada.
authors.forename: Sarah-Kim
authors.initials: SK
authors.lastname: Shields
authors.forename: Catalin
authors.initials: C
authors.lastname: Nicola
authors.forename: Chandan
authors.initials: C
authors.lastname: Chakraborty
mesh_terms: D036002:ADP Ribose Transferases / Q000494:pharmacology; D000577:Amides / Q000494:pharmacology; D001905:Botulinum Toxins / Q000494:pharmacology; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020868:Gene Silencing; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D007335:Insulin-Like Growth Factor II / Q000031:analogs & derivatives / Q000494:pharmacology / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D010446:Peptide Fragments / Q000494:pharmacology; D011034:Podophyllotoxin / Q000031:analogs & derivatives / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D011725:Pyridines / Q000494:pharmacology; D017526:Receptor, IGF Type 1 / Q000502:physiology*; D014327:Trophoblasts / Q000502:physiology*; D020764:cdc42 GTP-Binding Protein / Q000037:antagonists & inhibitors; D020830:rac1 GTP-Binding Protein / Q000037:antagonists & inhibitors; D020741:rho GTP-Binding Proteins / Q000235:genetics / Q000502:physiology*; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein / Q000235:genetics; D000075024:rhoC GTP-Binding Protein
chemical_list: D000577:Amides; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D010446:Peptide Fragments; D011725:Pyridines; C415032:picropodophyllin; C058957:insulin-like growth factor 1, des-(1-3)-; C066737:RHOA protein, human; C108830:Y 27632; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; D036002:ADP Ribose Transferases; C063007:exoenzyme C3, Clostridium botulinum; D017526:Receptor, IGF Type 1; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D001905:Botulinum Toxins; C066690:RHOC protein, human; D020764:cdc42 GTP-Binding Protein; D020830:rac1 GTP-Binding Protein; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein; D000075024:rhoC GTP-Binding Protein; D011034:Podophyllotoxin