The Interaction of Protein-tyrosine Phosphatase α (PTPα) and RACK1 Protein Enables Insulin-like Growth Factor 1 (IGF-1)-stimulated Abl-dependent and -independent Tyrosine Phosphorylation of PTP α

Protein tyrosine phosphatase alpha (PTP alpha) promotes integrinstimulated cell migration in part through the role of Src-phosphorylated PTP alpha-Tyr(P)-789 in recruiting and localizing p130Cas to focal adhesions. The growth factor IGF-1 also stimulatesPTP alpha-Tyr-789 phosphorylation to positively regulate cell movement. This is in contrast to integrin-induced PTP alpha phosphorylation, that induced by IGF-1 can occur in cells lacking Src family kinases (SFKs), indicating that an unknown kinase distinct from SFKs can target PTP alpha. We show that this IGF-1stimulated tyrosine kinase is Abl. We found that PTP alpha binds to the scaffold protein RACK1 and that RACK1 coordinates the IGF-1 receptor, PTP alpha, and Abl in a complex to enable IGF-1stimulated and Abl-dependent PTP alpha-Tyr-789 phosphorylation. In cells expressing SFKs, IGF-1-stimulated phosphorylation of PTP alpha is mediated by RACK1 but is Abl-independent. Furthermore, expressing the SFKs Src and Fyn in SFK-deficient cells switches IGF-1-induced PTP alpha phosphorylation to occur in an Abl-independent manner, suggesting that SFK activity dominantly regulates IGF-1/IGF-1 receptor signaling to PTP alpha. RACK1 is a molecular scaffold that integrates growth factor and integrin signaling, and our identification of PTP alpha as a RACK1 binding protein suggests that RACK1 may coordinate PTP alpha Tyr- 789 phosphorylation in these signaling networks to promote cell migration.