Abstract
The Src family kinases possess two sites of tyrosine phosphorylation that are critical to the regulation of kinase activity. Autophosphorylation on an activation loop tyrosine residue (Tyr 416 in commonly used chicken c-Src numbering) increases catalytic activity, while phosphorylation of a C-terminal tyrosine (Tyr 527 in c-Src) inhibits activity. The latter modification is achieved by the tyrosine kinase Csk (C-terminal Src Kinase), but the complete inactivation of the Src family kinases also requires the dephosphorylation of the activation loop tyrosine. The SH3 domain of Csk recruits the tyrosine phosphatase PEP, allowing for the coordinated inhibition of Src family kinase activity. We have discovered that Csk forms homodimers through interactions mediated by the SH3 domain in a manner that buries the recognition surface for SH3 ligands. The formation of this dimer would therefore block the recruitment of tyrosine phosphatases and may have important implications for the regulation of Src kinase activity.
Highlights
Members of the Src family of protein tyrosine kinases, such as cSrc, Lck, Fyn and Hck, are key players in many signalling pathways that regulate cell growth, proliferation and motility [1]
Autophosphorylation of the Src family kinases on Tyr 416, located within a central regulatory element in the kinase domain known as the activation loop, increases activity by stabilizing the kinase domain in a conformation that promotes catalysis [3]
The phosphorylation of Tyr 527 in the Cterminal tail of the Src family kinases by Csk (C-terminal Src Kinase) results in the intramolecular engagement of the tail by the Src Homology 2 (SH2) domain and the concomitant docking of the Src Homology 3 (SH3) domain onto the SH2-kinase linker, which together stabilize the kinase domain in an inactive conformation [4,5,6,7,8]
Summary
Members of the Src family of protein tyrosine kinases, such as cSrc, Lck, Fyn and Hck, are key players in many signalling pathways that regulate cell growth, proliferation and motility [1]. Full inactivation of the Src family kinases requires both dephosphorylation of the activation loop and phosphorylation of the C-terminal tail [9]. Unlike the Src family kinases, Csk is not constitutively membrane-localized, and the SH2 domain is required for the recruitment of Csk to the plasma membrane. In T-cells, Csk associates with the tyrosine phosphatase PEP, which dephosphorylates the activation loop of the Src family kinase Lck [16]. The association of Csk and PEP provides for a coordinated downregulation of Lck through simultaneous phosphorylation of the C-terminus and dephosphorylation of the activation loop. By interfering with the recruitment of tyrosine phosphatases, Csk dimerization could serve to modulate the degree of activation loop phosphorylation and activity of the Src family kinases
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