Lck promotes Zap70-dependent LAT phosphorylation by bridging Zap70 to LAT

0495490 - ÚMG 2019 RIV US eng J - Článek v odborném periodiku
Lo, W.L. - Shah, N.H. - Ahsan, N. - Horková, Veronika - Štěpánek, Ondřej - Salomon, A. R. - Kuriyan, J. - Weiss, A.
Lck promotes Zap70-dependent LAT phosphorylation by bridging Zap70 to LAT.
Nature Immunology. Roč. 19, č. 7 (2018), s. 733-741. ISSN 1529-2908. E-ISSN 1529-2916
Grant CEP: GA ČR GJ16-09208Y
Institucionální podpora: RVO:68378050
Klíčová slova: t-cell-receptor * phosphotyrosine-binding domain * lymphoproliferative disease * thymocyte development * structural basis * sh2 domain * in-vivo * activation * zap-70 * association
Obor OECD: Immunology
Impakt faktor: 23.530, rok: 2018

T cell-antigen receptor (TCR) signaling requires the sequential activities of the kinases Lck and Zap7O. Upon TCR stimulation, Lck phosphorylates the TCR, thus leading to the recruitment, phosphorylation, and activation of Zap7O. Lck binds and stabilizes phosho-Zap7O by using its SH2 domain, and Zap7O 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-Zap7O 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.
Trvalý link: http://hdl.handle.net/11104/0288463