Multiple signaling pathways are activated during insulin-like growth factor-I (IGF-I) stimulated breast cancer cell migration.
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.
Zhang
Xihong
X
Department of Medicine, University of Minnesota Cancer Center, Minneapolis, MN, 55455, USA.
Lin
Min
M
van Golen
Kenneth L
KL
Yoshioka
Kiyoko
K
Itoh
Kazuyuki
K
Yee
Douglas
D
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
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