title: Multiple signaling pathways are activated during insulin-like growth factor-I (IGF-I) stimulated breast cancer cell migration.
abstract: In order to display the full metastatic phenotype, the cancer cell must acquire the ability to migrate. In breast cancer, we have previously shown that insulin-like growth factor I (IGF-I) enhances cell motility in the highly metastatic MDA-231BO cell line by activating the type I IGF receptor (IGF1R). This motility response requires activation of IRS-2 and integrin ligation. In order to identify the key molecules downstream of IRS-2, we examined several signaling pathways known to be involved in cell motility. Focal adhesion kinase (FAK) was not activated by IGF-I, but IGF-I caused redistribution of FAK away from focal adhesion plaques. IGF-I treatment of MDA-231BO cells activated RhoA and inhibition of Rho-kinase (ROCK) inhibited the IGF-mediated motility response. The mitogen activated protein kinase (MAPK), p38, was also activated by IGF-I and inhibition of p38 by SB203580 blocked IGF-I induced cell motility. ROCK inhibition with Y-27632 also inhibited p38 phosphorylation suggesting that p38 lies downstream of ROCK. Both Erk1,2 and phosphatidyl-3 kinase (PI3K) were required for IGF-I stimulated cell motility, but only PI3K appeared to be directly downstream of IGF-I. Thus, IGF-I activation of its receptor coordinates multiple signaling pathways required for cell motility. Defining the key molecules downstream of the type I IGF receptor may provide a basis for optimizing therapies directed at this target.
authors.affiliation: Department of Medicine, University of Minnesota Cancer Center, Minneapolis, MN, 55455, USA.
authors.forename: Xihong
authors.initials: X
authors.lastname: Zhang
authors.forename: Min
authors.initials: M
authors.lastname: Lin
authors.forename: Kenneth L
authors.initials: KL
authors.lastname: van Golen
authors.forename: Kiyoko
authors.initials: K
authors.lastname: Yoshioka
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Itoh
authors.forename: Douglas
authors.initials: D
authors.lastname: Yee
mesh_terms: D000577:Amides / Q000494:pharmacology; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D015151:Immunoblotting; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D018613:Microscopy, Confocal; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D020741:rho GTP-Binding Proteins / Q000378:metabolism
chemical_list: D000577:Amides; D004791:Enzyme Inhibitors; D007093:Imidazoles; D011725:Pyridines; C108830:Y 27632; D007334:Insulin-Like Growth Factor I; D051417:Focal Adhesion Kinase 1; D020929:Mitogen-Activated Protein Kinase Kinases; D020741:rho GTP-Binding Proteins; C093642:SB 203580