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Protein Tyrosine Phosphatase Regulates Fyn Activity and Cbp/PAG Phosphorylation in Thymocyte Lipid Rafts¹

Lola Maksumova^*, Hoa T. Le, Farkhad Muratkhodjaev^*, Dominique Davidson, André Veillette and Catherine J. Pallen^2,*,

^* Department of Pediatrics and Departments of Pathology and Laboratory Medicine, British Columbia Research Institute for Children’s and Women’s Health, University of British Columbia, Vancouver, Canada; and Clinical Research Institute of Montreal, Montreal, Canada

A role for the receptor protein tyrosine phosphatase (PTP) in immune cell function and regulation of Src family kinases was investigated using thymocytes from PTP-deficient mice. PTP-null thymocytes develop normally, but unstimulated PTP^–/– cells exhibit increased tyrosine phosphorylation of specific proteins, increased Fyn activity, and hyperphosphorylation of Cbp/PAG that promotes its association with C-terminal Src kinase. Elevated Fyn activity in the absence of PTP is due to enhanced phosphorylation of Fyn tyrosines 528 and 417. Some PTP is localized in lipid rafts of thymocytes, and raft-associated Fyn is specifically activated in PTP^–/– cells. PTP is not a Cbp/PAG phosphatase, because it is not required for Cbp/PAG dephosphorylation in unstimulated or anti-CD3-stimulated thymocytes. Together, our results indicate that PTP, likely located in lipid rafts, regulates the activity of raft Fyn. In the absence of PTP this population of Fyn is activated and phosphorylates Cbp/PAG to enhance association with C-terminal Src kinase. Although TCR-mediated tyrosine phosphorylation was apparently unaffected by the absence of PTP, the long-term proliferative response of PTP^–/– thymocytes was reduced. These findings indicate that PTP is a component of the complex Src family tyrosine kinase regulatory network in thymocytes and is required to suppress Fyn activity in unstimulated cells in a manner that is not compensated for by the major T cell PTP and SFK regulator, CD45.

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