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A novel negative regulatory function of the phosphoprotein associated with glycosphingolipid-enriched microdomains: blocking Ras activation
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SYSNO ASEP 0085150 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Ostatní články Title A novel negative regulatory function of the phosphoprotein associated with glycosphingolipid-enriched microdomains: blocking Ras activation Title Nová negativní regulační funkce fosfoproteinu asociovaného s mikrodoménami obohacenými glykosfingolipidy: blokování aktivace Ras Author(s) Smida, M. (DE)
Posevitz-Fejfar, A. (DE)
Hořejší, Václav (UMG-J) RID
Schraven, B. (DE)
Lindquist, J.A. (DE)Source Title Blood. - : American Society of Hematology - ISSN 0006-4971
Roč. 110, č. 2 (2007), s. 596-605Number of pages 10 s. Language eng - English Country US - United States Keywords PAG ; Ras ; lipid rafts Subject RIV EB - Genetics ; Molecular Biology R&D Projects 1M0506 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) CEZ AV0Z50520514 - UMG-J (2005-2011) Annotation Analysis of anergic T cells revealed that adaptor protein 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 hyperactive conformation, thus explaining the enhanced Fyn kinase activity. In addition, we have also identified the formation of a multiprotein complex containing PAG, Fyn, Sam68, and RasGAP in stimulated T cells. PAG-Fyn overexpression is sufficient to suppress Ras activation in Jurkat T cells and 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, both enhanced Src kinase activity and Ras activation was demonstrated, thereby establishing PAG as an important negative regulator of T-cell activation. Workplace Institute of Molecular Genetics Contact Nikol Škňouřilová, nikol.sknourilova@img.cas.cz, Tel.: 241 063 217 Year of Publishing 2008
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