title: 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.
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.
authors.affiliation: From the Departments of Medicine and the Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia V5Z 4H4, Canada.
authors.forename: Ranvikram S
authors.initials: RS
authors.lastname: Khanna
authors.affiliation: the Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia V5Z 4H4, Canada Pediatrics and.
authors.forename: Hoa T
authors.initials: HT
authors.lastname: Le
authors.affiliation: the Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia V5Z 4H4, Canada Pediatrics and.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.affiliation: the Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia V5Z 4H4, Canada.
authors.forename: Thomas C H
authors.initials: TC
authors.lastname: Fung
authors.affiliation: the Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia V5Z 4H4, Canada Pediatrics and cpallen@mail.ubc.ca.
authors.forename: Catherine J
authors.initials: CJ
authors.lastname: Pallen
mesh_terms: D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D061986:MCF-7 Cells; D051379:Mice; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding; D016315:Proto-Oncogene Proteins c-abl / Q000235:genetics / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D034622:RNA Interference; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism; D054630:Receptor-Like Protein Tyrosine Phosphatases, Class 4 / Q000235:genetics / Q000378:metabolism*; D000075370:Receptors for Activated C Kinase; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D014443:Tyrosine / Q000378:metabolism; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D009363:Neoplasm Proteins; D011743:Pyrimidines; C419368:RACK1 protein, human; D000075370:Receptors for Activated C Kinase; D011956:Receptors, Cell Surface; D014443:Tyrosine; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1; D016315:Proto-Oncogene Proteins c-abl; D019061:src-Family Kinases; D054630:Receptor-Like Protein Tyrosine Phosphatases, Class 4; D019204:GTP-Binding Proteins; C498826:nilotinib
keywords: ABL Tyrosine Kinase; Fyn; IGF-1; Insulin-like Growth Factor (IGF); PTPα; Phosphotyrosine Signaling; Protein-tyrosine Phosphatase (Tyrosine Phosphatase); RACK1; Src