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UBC Theses and Dissertations

IGF-1 activates c-Abl to regulate PTPα tyrosine phosphorylation and cell migration Khanna, Ranvikram Singh


Protein tyrosine phosphorylation is an important cellular mechanism that regulates intracellular signalling pathways to control many cellular activities, including proliferation, growth and differentiation. Tyrosine phosphorylation is a reversible process regulated by protein tyrosine kinases and protein tyrosine phosphatases (PTPs) which add and remove phosphate groups from target proteins, respectively. PTPα, a receptor-type member of the classical subfamily of PTPs, functions to activate Src family kinases (SFKs). In integrin signaling, PTPα-activated SFKs act in conjunction with focal adhesion kinase (FAK) to phosphorylate PTPα at a tyrosine residue (Tyr789) near its C-terminus to enable PTPα-dependent promotion of cell migration. Recently, our lab also found that Tyr789 of PTPα is phosphorylated in response to various growth factor stimuli, including IGF-1. However, the kinase and mechanism underlying this growth factor-stimulated phosphorylation and its functional importance in cellular responses were unknown. I investigated IGF-1-dependent phosphorylation of PTPα in mouse embryo fibroblasts lacking the SFKs Src, Yes, and Fyn (SYF cells) and in the SH-SY5Y neuroblastoma cell line. I found that the tyrosine kinase c-Abl was responsible for IGF-1-induced PTPα Tyr789 phosphorylation, and that IGF-1 activated c-Abl. Furthermore, PTPα was found to exist in a constitutive multi-protein complex with RACK1 and the IGF-1R. IGF-1 stimulation resulted in RACK1-dependent recruitment of the kinase c-Abl and phosphorylation of Tyr789 of PTPα. IGF-1-induced migration of SYF cells was dependent upon PTPα Tyr789, and that of SH-SY5Y cells was dependent upon both c-Abl activity and PTPα. My study has revealed an IGF-1-dependent signaling mechanism involving a RACK1-scaffolded multi-protein complex of IGF-1R, c-Abl, and PTPα that regulates c-Abl activity and PTPα tyrosine phosphorylation to promote fibroblast and neuroblastoma cell migration. This is distinct from the integrin-stimulated SFK/FAK-dependent tyrosine phosphorylation of PTPα. Overall, my findings suggest that distinct receptor-mediated signaling pathways converge on PTPα to regulate its phosphorylation and promote cell migration. As aberrant IGF-1/IGF-1 receptor signaling is associated with tumourigenesis and metastasis of several types of cancers, further investigation into the role of IGF-1-regulated PTPα phosphorylation in neuroblastoma cells may reveal potential therapeutic targets for this pediatric tumour and also have broader relevance for the treatment of other types of cancer.

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