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A more recent version of this article appeared on September 1, 2003
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Submitted on April 17, 2003
Accepted on May 15, 2003
* Corresponding author. E-mail address: endo{at}med.unc.edu.
Growth factor signaling is usually analyzed in isolation without considering the effect of ligand occupancy of transmembrane proteins other than the growth factor receptors themselves. In smooth muscle cells (SMCs) the transmembrane protein SHPS-1 has been shown to be an important regulator of insulin-like growth factor-I (IGF-I) signaling. SHPS-1 is phosphorylated in response to IGF-I leading to recruitment of the tyrosine phosphatase, SHP-2. Subsequently, SHP-2 is transferred to IGF-I receptor (IGF-IR) and regulates the duration of IGF-IR phosphorylation. Whether ligand occupancy of SHPS-1 influences SHPS-1 phosphorylation or SHP-2 recruitment thereby altering growth factor signaling is unknown. Previous studies have shown that integrin associated protein (IAP) associates with SHPS-1. We undertook these studies to determine if this interaction controlled SHPS-1 phosphorylation and/or SHP-2 recruitment and thereby regulated IGF-I signaling.
Disruption of IAP-SHPS-1 binding, using an IAP mAb or cells expressing mutant forms of IAP that did not bind to SHPS-1, inhibited IGF-I stimulated SHPS-1 phosphorylation and SHP-2 recruitment. This was associated with a lack of SHP-2 transfer to IGF-IR and sustained receptor phosphorylation. This resulted in an inability of IGF-I to stimulate sustained MAP kinase activation, cell proliferation and cell migration. The effect was specific for IGF-I since disruption of the IAP/SHPS-1 interaction had no effect on PDGF stimulated SHPS-1 phosphorylation or cell migration.
In summary, our results show that 1) ligand occupancy of SHPS-1 is a key determinant of its ability to be phosphorylated following IGF-I stimulation and 2) the interaction between IAP and SHPS-1 is an important regulator of IGF-I signaling since disruption of the results in impaired SHP-2 recruitment and subsequent inhibition of IGF-I stimulated cell proliferation and migration.
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