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Blood, 15 July 2007, Vol. 110, No. 2, pp. 596-625.
Prepublished online as a Blood First Edition Paper on March 27, 2007; DOI 10.1182/blood-2006-07-038752.
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Submitted July 31, 2006
Accepted March 1, 2007
A novel negative regulatory function of PAG: blocking Ras activation
Michal Smida, Anita Posevitz-Fejfar, Vaclav Horejsi, Burkhart Schraven, and Jonathan A. Lindquist*
Institute of Immunology, Otto-von-Guericke Univeristy, Magdeburg, Germany
Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Prague, Czech Republic
* Corresponding author; email: jonathan.lindquist{at}medizin.uni-magdeburg.de.
In primary human T-cells, anergy induction results in enhanced p59Fyn activity. Since Fyn is the kinase primarily responsible for the phosphorylation of PAG (the phosphoprotein associated with glycosphingolipid-enriched microdomains), which negatively regulates Src-kinase activity by recruiting Csk (the C-terminal Src kinase) to the membrane, we investigated whether anergy induction also affects PAG. Analysis of anergic T-cells revealed that PAG is hyperphosphorylated at the Csk binding site, leading to enhanced Csk recruitment and inhibitory tyrosine phosphorylation within Fyn. This together with enhanced phosphorylation of a tyrosine within the SH2 domain of Fyn leads to the formation of a hyper-active conformation, thus explaining the enhanced Fyn kinase activity. Additionally, we have also identified the formation of a multi-protein complex containing PAG, Fyn, Sam68, and RasGAP in stimulated T-cells. We demonstrate that PAG-Fyn over-expression is sufficient to suppress Ras activation in Jurkat T-cells and show that this activity is independent of Csk binding. Thus, in addition to negatively regulating Src family kinases by recruiting Csk, PAG also negatively regulates Ras by recruiting RasGAP to the membrane. Finally, by knocking down PAG, we demonstrate both enhanced Src kinase activity and Ras activation, thereby establishing PAG as an important negative regulator of T-cell activation.
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