@article{13489c63805a450683e88579d9c78c5f,
title = "Lck promotes Zap70-dependent LAT phosphorylation by bridging Zap70 to LAT",
abstract = "T cell-antigen receptor (TCR) signaling requires the sequential activities of the kinases Lck and Zap70. Upon TCR stimulation, Lck phosphorylates the TCR, thus leading to the recruitment, phosphorylation, and activation of Zap70. Lck binds and stabilizes phosho-Zap70 by using its SH2 domain, and Zap70 phosphorylates the critical adaptors LAT and SLP76, which coordinate downstream signaling. It is unclear whether phosphorylation of these adaptors occurs through passive diffusion or active recruitment. We report the discovery of a conserved proline-rich motif in LAT that mediates efficient LAT phosphorylation. Lck associates with this motif via its SH3 domain, and with phospho-Zap70 via its SH2 domain, thereby acting as a molecular bridge that facilitates the colocalization of Zap70 and LAT. Elimination of this proline-rich motif compromises TCR signaling and T cell development. These results demonstrate the remarkable multifunctionality of Lck, wherein each of its domains has evolved to orchestrate a distinct step in TCR signaling.",
author = "Lo, {Wan Lin} and Shah, {Neel H.} and Nagib Ahsan and Veronika Horkova and Ondrej Stepanek and Salomon, {Arthur R.} and John Kuriyan and Arthur Weiss",
note = "Funding Information: We thank L. Samelson and C. Sommers (NIH) for sharing the LAT-deficient mouse line; T. Kadlecek for generating the J.Lck mutant Jurkat cell clone; A. Roque for animal husbandry; W. Paster (Medical University Vienna) for sharing the CD8 expression vector; T. Brdicka (IMG, Prague) for sharing the Lck-encoding DNA sequence; the UCSF Parnassus Flow Cytometry Core for maintaining FACSAria instruments and services; the NIH Tetramer Core Facility for providing the H-2Kb OVA tetramers and H-2Ab OVA tetramers; and D. L. Donermeyer, B. B. Au-Yeung, H. Wang, and C. Morley for critical reading of the manuscript and providing comments. This work was supported by the Jane Coffin Childs Fund 61-1560 (to W.-L.L.); the Damon Runyon Cancer Research Foundation 2198-14 (to N.H.S.); the Czech Science Foundation GJ16-09208Y (to O.S.); the Howard Hughes Medical Institute (to A.W. and J.K.); NIH, NIAID P01 AI091580-06 (to A.W., J.K., and A.R.S.); R01 AI083636 and P30 GM110759 (to A.R.S.); and DRC Center Grant P30 DK063720 (UCSF Parnassus Flow Cytometry Core). Publisher Copyright: {\textcopyright} 2018 The Author(s).",
year = "2018",
month = jul,
day = "1",
doi = "10.1038/s41590-018-0131-1",
language = "English",
volume = "19",
pages = "733--741",
journal = "Nature Immunology",
issn = "1529-2908",
publisher = "Nature Publishing Group",
number = "7",
}