The Journal of Experimental Medicine
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Published online March 12, 2007
doi:10.1084/jem.20062066
The Journal of Experimental Medicine, Vol. 204, No. 3, 681-691
The Rockefeller University Press, 0022-1007 $30.00
© 2007 Bartolo et al.
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ARTICLE

 A novel pathway down-modulating T cell activation involves HPK-1–dependent recruitment of 14-3-3 proteins on SLP-76

Vincenzo Di Bartolo1, Benjamin Montagne1, Mogjiborahman Salek3, Britta Jungwirth1, Florent Carrette1, Julien Fourtane1, Nathalie Sol-Foulon2, Frédérique Michel1, Olivier Schwartz2, Wolf D. Lehmann3, and Oreste Acuto1

1 Molecular Immunology Unit, Centre National de la Recherche Scientifique (CNRS) URA 1961, and 2 Virus and Immunity Group, CNRS URA 1930, Institut Pasteur, 75724 Paris, Cedex 15, France
3 Central Spectroscopy, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany

CORRESPONDENCE Vincenzo Di Bartolo: vbartolo{at}pasteur.fr

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 14-3-3{varepsilon} 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-{gamma}1. 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.

Abbreviations used: ERK, extracellular signal-regulated kinase; Gads, Grb2-related adaptor downstream of Shc; GST, glutathione-S-transferase; HPK-1, hematopoietic progenitor kinase 1; IRS, insulin receptor substrate; LAT, linker for activation of T cells; MALDI-TOF, matrix-assisted laser desorption and ionization time of flight; MAP4K, mitogen-activated protein kinase kinase kinase kinase; MS, mass spectrometry; nanoESI, nano-electrospray ionization; PKA, protein kinase A; PKC, protein kinase C; PLC, phospholipase C; PTP, protein tyrosine phosphatase; siRNA, small interfering RNA; SLP-76, SH2 domain–containing leukocyte protein of 76 kD.

V. Di Bartolo's present address is Lymphocyte Cell Biology Unit, Institut Pasteur, 75724 Paris, Cedex 15, France.

O. Acuto and M. Salek's present address is Sir William Dunn School of Pathology, University of Oxford, OX1 3RE Oxford, UK.


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