| First Author | Shen X | Year | 2012 |
| Journal | Mol Cell Biol | Volume | 32 |
| Issue | 20 | Pages | 4116-30 |
| PubMed ID | 22869525 | Mgi Jnum | J:189259 |
| Mgi Id | MGI:5444808 | Doi | 10.1128/MCB.01011-12 |
| Citation | Shen X, et al. (2012) Insulin-like growth factor (IGF) binding protein 2 functions coordinately with receptor protein tyrosine phosphatase beta and the IGF-I receptor to regulate IGF-I-stimulated signaling. Mol Cell Biol 32(20):4116-30 |
| abstractText | Insulin-like growth factor I (IGF-I) is a mitogen for vascular smooth muscle cells (VSMC) and has been implicated in the development and progression of atherosclerosis. IGF binding proteins (IGFBPs) modify IGF-I actions independently of IGF binding, but a receptor-based mechanism by which they function has not been elucidated. We investigated the role of IGFBP-2 and receptor protein tyrosine phosphatase beta (RPTPbeta) in regulating IGF-I signaling and cellular proliferation. IGFBP-2 bound RPTPbeta, which led to its dimerization and inactivation. This enhanced PTEN tyrosine phosphorylation and inhibited PTEN activity. Utilization of substrate trapping and phosphatase-dead mutants showed that RPTPbeta bound specifically to PTEN and dephosphorylated it. IGFBP-2 knockdown led to decreased PTEN tyrosine phosphorylation and decreased AKT Ser473 activation. IGFBP-2 enhanced IGF-I-stimulated VSMC migration and proliferation. Analysis of aortas obtained from IGFBP-2(-/-) mice showed that RPTPbeta was activated, and this was associated with inhibition of IGF-I stimulated AKT Ser473 phosphorylation and VSMC proliferation. These changes were rescued following administration of IGFBP-2. These findings present a novel mechanism for coordinate regulation of IGFBP-2 and IGF-I signaling functions that lead to stimulation of VSMC proliferation. The results have important implications for understanding how IGFBPs modulate the cellular response to IGF-I. |
