title: SKAP1 protein PH domain determines RapL membrane localization and Rap1 protein complex formation for T cell receptor (TCR) activation of LFA-1.
abstract: Although essential for T cell function, the identity of the T cell receptor (TCR) "inside-out" pathway for the activation of lymphocyte function-associated antigen 1 (LFA-1) is unclear. SKAP1 (SKAP-55) is the upstream regulator needed for TCR-induced RapL-Rap1 complex formation and LFA-1 activation. In this paper, we show that SKAP1 is needed for RapL binding to membranes in a manner dependent on the PH domain of SKAP1 and the PI3K pathway. A SKAP1 PH domain-inactivating mutation (i.e. R131M) markedly impaired RapL translocation to membranes for Rap1 and LFA-1 binding and the up-regulation of LFA-1-intercellular adhesion molecule 1 (ICAM-1) binding. Further, N-terminal myr-tagged SKAP1 for membrane binding facilitated constitutive RapL membrane and Rap1 binding and effectively substituted for PI3K and TCR ligation in the activation of LFA-1 in T cells.
authors.affiliation: Department of Pathology, University of Cambridge, Cambridge, United Kingdom. moniraab@yahoo.com.
authors.forename: Monika
authors.initials: M
authors.lastname: Raab
authors.forename: Xin
authors.initials: X
authors.lastname: Smith
authors.forename: Yves
authors.initials: Y
authors.lastname: Matthess
authors.forename: Klaus
authors.initials: K
authors.lastname: Strebhardt
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Rudd
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D019169:Jurkat Cells; D016169:Lymphocyte Function-Associated Antigen-1 / Q000096:biosynthesis* / Q000235:genetics; D020559:Monomeric GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D021381:Protein Transport / Q000502:physiology; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000378:metabolism*; D000089804:Shelterin Complex; D013601:T-Lymphocytes / Q000378:metabolism*; D034501:Telomere-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000502:physiology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D018799:Intercellular Adhesion Molecule-1; D016169:Lymphocyte Function-Associated Antigen-1; D020559:Monomeric GTP-Binding Proteins; D046912:Multiprotein Complexes; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D011948:Receptors, Antigen, T-Cell; D000089804:Shelterin Complex; D034501:Telomere-Binding Proteins; C454042:RASSF5 protein, human; C108336:SKAP1 protein, human; C440809:TERF2IP protein, human