Protein tyrosine phosphatase alpha (PTP) is a widely expressed receptor-type phosphatase that functions in multiple signaling systems. The actions of PTP can be regulated by its phosphorylation on serine and tyrosine residues, although little is known about the conditions that promote PTP phosphorylation. In this study, we tested the ability of several extracellular factors to stimulate PTP tyrosine phosphorylation. The growth factors IGF-1 and acidic FGF induced the highest increase in PTP phosphorylation at tyrosine 789, followed by PMA and LPA, while EGF had little effect. Further investigation of IGF-1-induced PTP tyrosine phosphorylation demonstrated that this occurs through a novel Src family kinase-independent mechanism that does not require focal adhesion kinase, PI 3-kinase, or MEK. We also show that PTP physically interacts with the IGF-1 receptor. In contrast to IGF-1-induced PTP phosphorylation, this association does not require IGF-1. The interaction of PTP and the IGF-1 receptor is independent of PTP catalytic activity, and expression of exogenous PTP does not promote IGF-1 receptor tyrosine dephosphorylation, indicating that PTP does not act as an IGF-1 receptor phosphatase. However, PTP mediates IGF-1 signaling, as IGF-1-stimulated fibroblast migration was reduced by ~50% in cells lacking PTP or in cells with mutant PTP lacking the tyrosine 789 phosphorylation site. Our results suggest that PTP tyrosine phosphorylation can occur in response to diverse stimuli and can be mediated by various tyrosine kinases. In the case of IGF-1, we propose that IGF-1-induced tyrosine 789 phosphorylation of PTP, possibly catalyzed by the PTP-associated IGF-1 receptor tyrosine kinase, is required for efficient cell migration in response to this growth factor.