Three cellular proteins that associate with the protein-tyrosine kinase, C-terminal Src kinase (Csk)
Abstract
Many signaling pathways are mediated through the Src-related PTKs in diverse cell types. Although the regulation of the Src-related PTKs is not completely defined, it is now evident that this family of PTKs is inhibited as a consequence of being phosphorylated by a nonreceptor PTK known as C-terminal Src kinase (Csk). The inhibition of the Src-related PTKs through phosphorylation by Csk, has proven to be essential for neural development because the targeted disruption of the csk gene results in embryonic lethality. The data contained in recent reports illustrate the importance of inhibiting Src-related PTKs through the targeting of Csk to cellular sites where activated Src-related PTKs reside. Results shown in this thesis demonstrate that Csk associates with three cellular proteins, p44, p36, and p15. The formation as well as the function of the Csk/p36 complex was studied in detail because signaling through Fc$\gamma$RIIA receptors specifically induced the formation of the Csk/p36 complex. Cell signaling induced the tyrosine phosphorylation of p36 which enabled it to associate with Csk. The association between Csk and tyrosine phosphorylated p36 required the presence of the SH2 domain of Csk. The formation of the Csk/tyrosine phosphorylated p36 complex caused the translocation of cytosolic Csk to the cellular membrane where its physiological substrates reside. Thus, this translocation provided Csk direct access to the Src-related PTKs and a mechanism whereby Csk could terminate signaling events generated through the activation of the Src-related PTKs. Studying the function of the Csk/p36 complex has yielded valuable insights into how Csk participates in cell signaling events mediated by the Src-related PTKs. The physiologically relevant targeting of Csk to cellular sites where activated Src-related PTKs reside, requires the cell signaling-induced formation of the Csk/tyrosine phosphorylated p36 complex which results in the translocation of cytosolic Csk to the cellular membrane. Thus, the ongoing research investigating the cell-signaling induced interactions between Csk and other cellular proteins promises to be very rewarding. And soon, the current mystery of how Csk participates in cell signaling pathways mediated through the Src-related PTKs will be solved.
Degree
Ph.D.
Advisors
Harrison, Purdue University.
Subject Area
Biochemistry
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