Src family protein tyrosine kinases are involved in the regulation of a large number of cellular processes in response to extracellular stimuli. Their crucial role in the initiation of cellular activation of T-lymphocytes following stimulation of the T-cell receptor by an antigen has sparked great interest in better understanding the regulation of their catalytic activity and function. The protein tyrosine kinase Csk is the major negative regulator of Src-related kinases through its ability to phosphorylate a negative regulatory tyrosine, in their carboxy-terminal region. By virtue of its negative impact on Src-like enzymes, Csk is capable of down-regulating T-cell activation. Nevertheless, the mechanisms regulating the inhibition of T-cell receptor signalling by Csk are still poorly understood. The experiments presented in this thesis were aimed at improving our understanding of the regulation of Csk in T-lymphocytes. I have demonstrated that the SH3 and SH2 domains of Csk, which can mediate protein-protein interactions, are essential for its capacity to down-regulate T-cell activation. This observation led me to the identification of the first known ligand for the SH3 domain of Csk, the protein tyrosine phosphatase, PEP. Functional analysis of the Csk-PEP complex revealed that these two enzymes cooperate to inhibit signals generated by Src-related enzymes, thereby acting as potent negative regulators of T-cell activation. Taken together, the results obtained suggest that the inhibitory function of Csk is not only dependent on its ability to phosphorylate the carboxy-terminal tyrosine of Src-related enzymes, but also relates to its ability to associate with the protein tyrosine phosphatase PEP.* / *Originally published in DAI Vol. 61, No. 6. Reprinted here with corrected author name.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.35865 |
| Date | January 1998 |
| Creators | Cloutier, Jean-Francois, 1971- |
| Contributors | Veillette, Andre (advisor) |
| Publisher | McGill University |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | application/pdf |
| Coverage | Doctor of Philosophy (Division of Experimental Medicine.) |
| Rights | All items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated. |
| Relation | alephsysno: 001652195, proquestno: NQ50132, Theses scanned by UMI/ProQuest. |
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