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.

• MeSH
• adaptorové proteiny signální transdukční chemie   metabolismus   MeSH
• aminokyselinové motivy MeSH
• fosforylace MeSH
• HEK293 buňky MeSH
• Jurkat buňky MeSH
• lidé MeSH
• membránové proteiny chemie   metabolismus   MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• prolin analýza   MeSH
• protein-tyrosinkináza ZAP-70 metabolismus   MeSH
• receptory antigenů T-buněk metabolismus   MeSH
• thymus imunologie   MeSH
• tyrosinkinasa p56(lck), specifická pro lymfocyty metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH