Protein tyrosine phosphatase-alpha complexes with the IGF-I receptor and undergoes IGF-I-stimulated tyrosine phosphorylation that mediates cell migration.
Protein tyrosine phosphatase-alpha (PTPalpha) is a widely expressed receptor-type phosphatase that functions in multiple signaling systems. The actions of PTPalpha can be regulated by its phosphorylation on serine and tyrosine residues, although little is known about the conditions that promote PTPalpha phosphorylation. In this study, we tested the ability of several extracellular factors to stimulate PTPalpha tyrosine phosphorylation. The growth factors IGF-I and acidic FGF induced the highest increase in PTPalpha phosphorylation at tyrosine 789, followed by PMA and lysophosphatidic acid, while EGF had little effect. Further investigation of IGF-I-induced PTPalpha tyrosine phosphorylation demonstrated that this occurs through a novel Src family kinase-independent mechanism that does not require focal adhesion kinase, phosphatidylinositol 3-kinase, or MEK. We also show that PTPalpha physically interacts with the IGF-I receptor. In contrast to IGF-I-induced PTPalpha phosphorylation, this association does not require IGF-I. The interaction of PTPalpha and the IGF-I receptor is independent of PTPalpha catalytic activity, and expression of exogenous PTPalpha does not promote IGF-I receptor tyrosine dephosphorylation, indicating that PTPalpha does not act as an IGF-I receptor phosphatase. However, PTPalpha mediates IGF-I signaling, because IGF-I-stimulated fibroblast migration was reduced by approximately 50% in cells lacking PTPalpha or in cells with mutant PTPalpha lacking the tyrosine 789 phosphorylation site. Our results suggest that PTPalpha tyrosine phosphorylation can occur in response to diverse stimuli and can be mediated by various tyrosine kinases. In the case of IGF-I, we propose that IGF-I-induced tyrosine 789 phosphorylation of PTPalpha, possibly catalyzed by the PTPalpha-associated IGF-I receptor tyrosine kinase, is required for efficient cell migration in response to this growth factor.
Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
Shirley C
SC
Chen
Ranvikram S
RS
Khanna
Darrell C
DC
Bessette
Lionel A
LA
Samayawardhena
Catherine J
CJ
Pallen
D000818:Animals; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000378:metabolism; D016220:Fibroblast Growth Factor 1 / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology*; D051417:Focal Adhesion Kinase 1 / Q000235:genetics / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D008246:Lysophospholipids / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D051076:Proto-Oncogene Proteins c-fyn / Q000235:genetics / Q000378:metabolism; D051575:Proto-Oncogene Proteins c-yes / Q000235:genetics / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000378:metabolism*; D054630:Receptor-Like Protein Tyrosine Phosphatases, Class 4 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014162:Transfection; D014443:Tyrosine; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism
D008246:Lysophospholipids; D016220:Fibroblast Growth Factor 1; D014443:Tyrosine; D004815:Epidermal Growth Factor; D007334:Insulin-Like Growth Factor I; D019869:Phosphatidylinositol 3-Kinases; D017526:Receptor, IGF Type 1; D051417:Focal Adhesion Kinase 1; C494960:Fyn protein, mouse; D051076:Proto-Oncogene Proteins c-fyn; D051575:Proto-Oncogene Proteins c-yes; C496051:Ptk2 protein, mouse; C496639:Yes1 protein, mouse; D019061:src-Family Kinases; D020928:Mitogen-Activated Protein Kinases; C516843:Ptpra protein, mouse; D054630:Receptor-Like Protein Tyrosine Phosphatases, Class 4; D013755:Tetradecanoylphorbol Acetate; C032881:lysophosphatidic acid