Phosphoprotein Associated with Glycosphingolipid-Enriched Microdomains (Pag), a Novel Ubiquitously Expressed Transmembrane Adaptor Protein, Binds the Protein Tyrosine Kinase Csk and Is Involved in Regulation of T Cell Activation

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  • Tomás̆ Brdic̆ka
    aInstitute of Molecular Genetics, Academy of Sciences of the Czech Republic, 14220 Prague, Czech Republic
  • Dagmar Pavlis̆tová
    aInstitute of Molecular Genetics, Academy of Sciences of the Czech Republic, 14220 Prague, Czech Republic
  • Albrecht Leo
    bImmunomodulation Laboratory of the Institute for Immunology, Ruprecht-Karls University Heidelberg, 69120 Heidelberg, Germany
  • Eddy Bruyns
    bImmunomodulation Laboratory of the Institute for Immunology, Ruprecht-Karls University Heidelberg, 69120 Heidelberg, Germany
  • Vladimír Kor̆ínek
    aInstitute of Molecular Genetics, Academy of Sciences of the Czech Republic, 14220 Prague, Czech Republic
  • Pavla Angelisová
    aInstitute of Molecular Genetics, Academy of Sciences of the Czech Republic, 14220 Prague, Czech Republic
  • Jeanette Scherer
    bImmunomodulation Laboratory of the Institute for Immunology, Ruprecht-Karls University Heidelberg, 69120 Heidelberg, Germany
  • Andrej Shevchenko
    cPeptide and Protein Group, European Molecular Biology Laboratory, 69012 Heidelberg, Germany
  • Anna Shevchenko
    cPeptide and Protein Group, European Molecular Biology Laboratory, 69012 Heidelberg, Germany
  • Ivan Hilgert
    aInstitute of Molecular Genetics, Academy of Sciences of the Czech Republic, 14220 Prague, Czech Republic
  • Jan C̆erný
    aInstitute of Molecular Genetics, Academy of Sciences of the Czech Republic, 14220 Prague, Czech Republic
  • Karel Drbal
    aInstitute of Molecular Genetics, Academy of Sciences of the Czech Republic, 14220 Prague, Czech Republic
  • Yasuhiro Kuramitsu
    bImmunomodulation Laboratory of the Institute for Immunology, Ruprecht-Karls University Heidelberg, 69120 Heidelberg, Germany
  • Birgit Kornacker
    bImmunomodulation Laboratory of the Institute for Immunology, Ruprecht-Karls University Heidelberg, 69120 Heidelberg, Germany
  • Václav Hor̆ejs̆í
    aInstitute of Molecular Genetics, Academy of Sciences of the Czech Republic, 14220 Prague, Czech Republic
  • Burkhart Schraven
    bImmunomodulation Laboratory of the Institute for Immunology, Ruprecht-Karls University Heidelberg, 69120 Heidelberg, Germany

Abstract

<jats:p>According to a recently proposed hypothesis, initiation of signal transduction via immunoreceptors depends on interactions of the engaged immunoreceptor with glycosphingolipid-enriched membrane microdomains (GEMs). In this study, we describe a novel GEM-associated transmembrane adaptor protein, termed phosphoprotein associated with GEMs (PAG). PAG comprises a short extracellular domain of 16 amino acids and a 397-amino acid cytoplasmic tail containing ten tyrosine residues that are likely phosphorylated by Src family kinases. In lymphoid cell lines and in resting peripheral blood α/β T cells, PAG is expressed as a constitutively tyrosine-phosphorylated protein and binds the major negative regulator of Src kinases, the tyrosine kinase Csk. After activation of peripheral blood α/β T cells, PAG becomes rapidly dephosphorylated and dissociates from Csk. Expression of PAG in COS cells results in recruitment of endogenous Csk, altered Src kinase activity, and impaired phosphorylation of Src-specific substrates. Moreover, overexpression of PAG in Jurkat cells downregulates T cell receptor–mediated activation of the transcription factor nuclear factor of activated T cells. These findings collectively suggest that in the absence of external stimuli, the PAG–Csk complex transmits negative regulatory signals and thus may help to keep resting T cells in a quiescent state.</jats:p>

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