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 PTPα

Ranvikram S Khanna,Hoa T Le,Jing Wang,Thomas C.H Fung,Catherine J Pallen

doi:10.1074/jbc.m114.624247

Abstract

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

Highlights

Insulin-like growth factor 1 (IGF-1) stimulates PTP␣ tyrosine phosphorylation to enhance cell migration
Abl Is Required for IGF-1-stimulated Tyrosine Phosphorylation of PTP␣ in SYF Fibroblasts—IGF-1 induces the robust phosphorylation of PTP␣ at Tyr-789 in SYF fibroblasts that lack the Src family kinase members Src, Yes, and Fyn, and this is independent of IGF-1-induced PI3K and MAPK signaling [9]
In the RACK1-coordinated signaling complex that we characterized in SYF cells, the transmembrane molecules IGF-1R␤ and PTP␣ are constitutively associated with RACK1 in a manner unaltered by the presence or absence of the growth factor IGF-1 or by the activity status of Abl

Summary

Introduction

Insulin-like growth factor 1 (IGF-1) stimulates PTP␣ tyrosine phosphorylation to enhance cell migration. The growth factor IGF-1 stimulates PTP␣-Tyr-789 phosphorylation to positively regulate cell movement This is in contrast to integrin-induced PTP␣ 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␣. We show that this IGF-1stimulated tyrosine kinase is Abl. We found that PTP␣ binds to the scaffold protein RACK1 and that RACK1 coordinates the IGF-1 receptor, PTP␣, and Abl in a complex to enable IGF-1stimulated and Abl-dependent PTP␣-Tyr-789 phosphorylation. RACK1 is a molecular scaffold that integrates growth factor and integrin signaling, and our identification of PTP␣ as a RACK1 binding protein suggests that RACK1 may coordinate PTP␣Tyr-789 phosphorylation in these signaling networks to promote cell migration

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Conclusion