title: Insulin-like growth factor (IGF) binding protein 2 functions coordinately with receptor protein tyrosine phosphatase β and the IGF-I receptor to regulate IGF-I-stimulated signaling.
abstract: 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 β (RPTPβ) in regulating IGF-I signaling and cellular proliferation. IGFBP-2 bound RPTPβ, 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 RPTPβ 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 RPTPβ 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.
authors.affiliation: Department of Medicine, University of North Carolina, School of Medicine, Chapel Hill, North Carolina, USA.
authors.forename: Xinchun
authors.initials: X
authors.lastname: Shen
authors.forename: Gang
authors.initials: G
authors.lastname: Xi
authors.forename: Laura A
authors.initials: LA
authors.lastname: Maile
authors.forename: Christine
authors.initials: C
authors.lastname: Wai
authors.forename: Clifford J
authors.initials: CJ
authors.lastname: Rosen
authors.forename: David R
authors.initials: DR
authors.lastname: Clemmons
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D018971:Insulin-Like Growth Factor Binding Protein 2 / Q000235:genetics / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000378:metabolism*; D054633:Receptor-Like Protein Tyrosine Phosphatases, Class 5 / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D018971:Insulin-Like Growth Factor Binding Protein 2; D012694:Serine; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1; D054633:Receptor-Like Protein Tyrosine Phosphatases, Class 5; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse