title: The alphaVbeta3 integrin regulates insulin-like growth factor I (IGF-I) receptor phosphorylation by altering the rate of recruitment of the Src-homology 2-containing phosphotyrosine phosphatase-2 to the activated IGF-I receptor.
abstract: The alphaVbeta3 integrin is an important determinant of IGF-I-stimulated receptor phosphorylation and biological actions. Blocking ligand occupancy of alphaVbeta3 with the distintegrin echistatin reduces IGF-I-stimulated receptor phosphorylation, and it inhibits cellular migration and DNA synthesis responses to IGF-I. We have shown that recruitment of the tyrosine phosphatase Src-homology 2-containing phosphotyrosine phosphatase-2 (SHP-2) to the IGF-I receptor (IGF-IR) is an important determinant of the duration of IGF-IR phosphorylation. These studies were undertaken to determine whether an alteration in the recruitment of SHP-2 to the receptor in the presence of echistatin could account for the decrease in receptor phosphorylation. Following an overnight exposure of smooth muscle cell cultures to echistatin, the addition of IGF-I was accompanied by rapid dephosphorylation of IGF-IR compared with cells exposed to media alone. This was associated with an increase in the rate of SHP-2 recruitment to the IGF-IR. In cells expressing a catalytically inactive form of SHP-2, prior exposure to echistatin had no effect on the rate of receptor dephosphorylation. In contrast to the usual physiologic situation in which following IGF-I exposure SHP-2 is recruited to IGF-IR via SHP-2 substrate-1 (SHPS-1) in the presence of echistatin, SHPS-1 was not used for SHP-2 recruitment. Our findings show that IRS-1 may substitute for SHPS-1 under these conditions. These results demonstrate that the activation state of alphaVbeta3 is an important regulator of the duration of IGF-IR phosphorylation and subsequent downstream signaling and that this regulation is mediated through changes in the subcellular localization of SHP-2.
authors.affiliation: University of North Carolina Department of Medicine, Division of Endocrinology and Metabolism, Chapel Hill, North Carolina 27599-7170, USA.
authors.forename: Laura A
authors.initials: LA
authors.lastname: Maile
authors.forename: David R
authors.initials: DR
authors.lastname: Clemmons
mesh_terms: D000943:Antigens, Differentiation; D015870:Gene Expression; D006801:Humans; D007163:Immunosorbent Techniques; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D039302:Integrin alphaVbeta3 / Q000502:physiology*; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D007700:Kinetics; D008562:Membrane Glycoproteins / Q000378:metabolism; D016296:Mutagenesis; D039842:Neural Cell Adhesion Molecule L1 / Q000378:metabolism; D010455:Peptides / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D054648:Protein Phosphatase 2; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D017526:Receptor, IGF Type 1 / Q000378:metabolism*; D011971:Receptors, Immunologic; D054593:SH2 Domain-Containing Protein Tyrosine Phosphatases; D014162:Transfection; D018909:src Homology Domains
chemical_list: D000943:Antigens, Differentiation; D007334:Insulin-Like Growth Factor I; D039302:Integrin alphaVbeta3; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D039842:Neural Cell Adhesion Molecule L1; D010455:Peptides; D019869:Phosphatidylinositol 3-Kinases; D054648:Protein Phosphatase 2; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases; D017526:Receptor, IGF Type 1; D011971:Receptors, Immunologic; D054593:SH2 Domain-Containing Protein Tyrosine Phosphatases; C501920:SIRPA protein, human; C057986:echistatin; C516724:PTPN11 protein, human