The Coordinate Cellular Response to Insulin-Like Growth Factor-I (IGF-I) and Insulin-Like Growth Factor Binding Protein-2 (IGFBP-2) Is Regulated Through Vimentin Binding to Receptor Tyrosine Phosphatase {beta} (RPTP{beta}) [Cell Biology]

March 18th, 2015 by Shen, X., Xi, G., Wai, C., Clemmons, D. R.

IGFBP-2 functions coordinately with IGF-I to stimulate cellular proliferation and differentiation. IGFBP-2 binds to RPTPβ and this binding in conjunction with IGF-I receptor stimulation induces RPTPβ polymerization leading to PTEN inactivation, AKT stimulation and enhanced cell proliferation. To determine the mechanism by which RPTPβ polymerization is regulated, we analyzed the protein(s) that associated with RPTPβ in response to IGF-I and IGFBP-2 in vascular smooth muscle cells. Proteomic experiments revealed that IGF-I stimulated the intermediate filament protein vimentin to bind to RPTPβ and knockdown of vimentin resulted in failure of IGFBP-2 and IGF-I to stimulate RPTPβ polymerization. Knockdown of IGFBP-2 or inhibition of IGF-IR tyrosine kinase disrupted vimentin/RPTPβ association. Vimentin binding to RPTPβ was mediated through vimentin serine phosphorylation. The serine threonine kinase, PKCζ, was recruited to vimentin in response to IGF-I and inhibition of PKCζ activation blocked these signaling events. A cell permeable peptide that contained the vimentin phosphorylation site disrupted vimentin/RPTPβ association and IGF-I stimulated RPTPβ polymerization and AKT activation. Integrin linked kinase (ILK) recruited to vimentin in response to IGF-I and inhibition of ILK/PKCζ association thereby reducing vimentin serine phosphorylation. PKCζ stimulation of vimentin phosphorylation required high glucose concentration and vimentin/ association only during hyperglycemia and disruption of vimetin/RPTPβ in diabetic mice inhibited RPTPβ polymerization, vimentin serine phosphorylation and AKT activation in response to IGF-I whereas non-diabetic mice showed no difference. The induction of vimentin phosphorylation is important for IGFBP-2 mediated enhancement of IGF-I-stimulated proliferation during hyperglycemia and it coordinates signaling between these two receptor -linked signaling systems.
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