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The Association between Integrin-associated Protein and SHPS-1 Regulates Insulin-like Growth Factor-I Receptor Signaling in Vascular Smooth Muscle Cells
Laura A. Maile,
Jane Badley-Clarke, and
David R. Clemmons *
Division of Endocrinology, University of North Carolina, Chapel Hill, North Carolina 27599-7170
Received for publication April 17, 2003.
Revision received May 14, 2003.
Accepted for publication May 15, 2003.
Monitoring Editor: Carl-Henrik Heldin
Growth factor signaling is usually analyzed in isolation withoutconsidering the effect of ligand occupancy of transmembraneproteins other than the growth factor receptors themselves.In smooth muscle cells, the transmembrane protein Src homology2 domain containing protein tyrosine phosphatase substrate-1(SHPS-1) has been shown to be an important regulator of insulin-likegrowth factor-I (IGF-I) signaling. SHPS-1 is phosphorylatedin response to IGF-I, leading to recruitment of Src homology2 domain tyrosine phosphatase (SHP-2). Subsequently, SHP-2 istransferred to IGF-I receptor and regulates the duration ofIGF-I receptor phosphorylation. Whether ligand occupancy ofSHPS-1 influences SHPS-1 phosphorylation or SHP-2 recruitment,thereby altering growth factor signaling, is unknown. Previousstudies have shown that integrin associated protein (IAP) associateswith SHPS-1. We undertook these studies to determine whetherthis interaction controlled SHPS-1 phosphorylation and/or SHP-2recruitment and thereby regulated IGF-I signaling. Disruptionof IAP-SHPS-1 binding, by using an IAP monoclonal antibody orcells expressing mutant forms of IAP that did not bind to SHPS-1,inhibited IGF-Istimulated SHPS-1 phosphorylation andSHP-2 recruitment. This was associated with a lack of SHP-2transfer to IGF-I receptor and sustained receptor phosphorylation.This resulted in an inability of IGF-I to stimulate sustainedmitogen-activated protein kinase activation, cell proliferation,and cell migration. The effect was specific for IGF-I becausedisruption of the IAPSHPS-1 interaction had no effecton platelet-derived growth factor-stimulated SHPS-1 phosphorylationor cell migration. In summary, our results show that 1) ligandoccupancy of SHPS-1 is a key determinant of its ability to bephosphorylated after IGF-I stimulation, and 2) the interactionbetween IAP and SHPS-1 is an important regulator of IGF-I signalingbecause disruption of the results in impaired SHP-2 recruitmentand subsequent inhibition of IGF-Istimulated cell proliferationand migration.