title: A novel pathway down-modulating T cell activation involves HPK-1-dependent recruitment of 14-3-3 proteins on SLP-76.
abstract: The SH2 domain-containing leukocyte protein of 76 kD (SLP-76) is a pivotal element of the signaling machinery controlling T cell receptor (TCR)-mediated activation. Here, we identify 14-3-3epsilon and zeta proteins as SLP-76 binding partners. This interaction was induced by TCR ligation and required phosphorylation of SLP-76 at serine 376. Ribonucleic acid interference and in vitro phosphorylation experiments showed that serine 376 is the target of the hematopoietic progenitor kinase 1 (HPK-1). Interestingly, either S376A mutation or HPK-1 knockdown resulted in increased TCR-induced tyrosine phosphorylation of SLP-76 and phospholipase C-gamma1. Moreover, an SLP-76-S376A mutant induced higher interleukin 2 gene transcription than wild-type SLP-76. These data reveal a novel negative feedback loop involving HPK-1-dependent serine phosphorylation of SLP-76 and 14-3-3 protein recruitment, which tunes T cell activation.
authors.affiliation: Molecular Immunology Unit, Centre National de la Recherche Scientifique (CNRS) URA 1961, Institut Pasteur, 75724 Paris, Cedex 15, France. vbartolo@pasteur.fr
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Di Bartolo
authors.forename: Benjamin
authors.initials: B
authors.lastname: Montagne
authors.forename: Mogjiborahman
authors.initials: M
authors.lastname: Salek
authors.forename: Britta
authors.initials: B
authors.lastname: Jungwirth
authors.forename: Florent
authors.initials: F
authors.lastname: Carrette
authors.forename: Julien
authors.initials: J
authors.lastname: Fourtane
authors.forename: Nathalie
authors.initials: N
authors.lastname: Sol-Foulon
authors.forename: Frédérique
authors.initials: F
authors.lastname: Michel
authors.forename: Olivier
authors.initials: O
authors.lastname: Schwartz
authors.forename: Wolf D
authors.initials: WD
authors.lastname: Lehmann
authors.forename: Oreste
authors.initials: O
authors.lastname: Acuto
mesh_terms: D048948:14-3-3 Proteins / Q000378:metabolism*; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D015536:Down-Regulation / Q000276:immunology*; D006801:Humans; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000276:immunology*; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding / Q000276:immunology; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism
chemical_list: D048948:14-3-3 Proteins; D048868:Adaptor Proteins, Signal Transducing; D010750:Phosphoproteins; C092947:SLP-76 signal Transducing adaptor proteins; D012694:Serine; C102102:hematopoietic progenitor kinase 1; D017346:Protein Serine-Threonine Kinases