PathwayStep6466 PathwayStep6465 PathwayStep6468 PathwayStep6467 PathwayStep6462 PathwayStep6461 PathwayStep6464 PathwayStep6463 PathwayStep6460 PathwayStep6459 PathwayStep6475 PathwayStep6474 PathwayStep6473 PathwayStep6472 PathwayStep6471 PathwayStep6470 PathwayStep6469 Phosphorylation of TBSMs in LAT Recruitment of Gads to LAT Recruitment of SLP-76 to Gads Translocation of PLC-gamma1 to PIP2 Disassociation of PLC-gamma1 from SLP-76 Disassociation of PLC-gamma1 from LAT Phosphorylation of PLC-gamma1 Recruitment of PLC-gamma1 to LAT Recruitment of PLC-gamma1 to SLP-76 Recruitment of ITK to SLP-76 Phosphorylation of SLP-76 PLC-gamma1 hydrolyses PIP2 p-SLP-76:ADAP binds Ena/VASP p-SLP-76 binds ADAP NCK binds PAK p-SLP-76 binds NCK NCK recruits WASP Generation of second messenger molecules Authored: Rudd, C.E., de Bono, B, Garapati, P V, 2008-01-24 15:53:10 In addition to serving as a scaffold via auto-phosphorylation, ZAP-70 also phosphorylates a restricted set of substrates following TCR stimulation - including LAT and SLP-76. These substrates have been recognized to play pivotal role in TCR signaling by releasing second messengers. When phosphorylated, LAT and SLP-76 act as adaptor proteins which serve as nucleation points for the construction of a higher order signalosome: GADS, PLC-gamma1 and GRB2 bind to the LAT on the phosphorylated tyrosine residues (steps 8 and 13). SLP-76 and SOS are then moved to the signalosome by interacting with the SH3 domains of GRB2 and GADS via their proline rich sequences (step 9). Three SLP-76 acidic domain N-term tyrosine residues are phosphorylated by ZAP-70, once SLP-76 binds to GADS (step 10). These phospho-tyrosine residues act as binding sites to the SH2 domains of PLC-gamma1, Vav and Itk (steps 11 and 12). <p>PLC-gamma1 is activated by dual phosphorylation on the tyrosine residues at positions 771, 783 and 1254 by Itk and ZAP-70 (step 14). Phosphorylated PLC-gamma1 subsequently detaches from LAT and SLP-76 and translocates to the plasma membrane by binding to phosphatidylinositol-4,5-bisphosphate (PIP2) via its PH domain (step 15). PLC-gamma1 goes on to hydrolyse PIP2 to second messengers DAG and IP3. These second messengers are involved in PKC and NF-kB activation and calcium mobilization (step 16). Pubmed15084594 Reactome Database ID Release 43202433 Reactome, http://www.reactome.org ReactomeREACT_12623 Reviewed: Trowsdale, J, 2008-02-26 12:02:59