PathwayStep6457 PathwayStep6456 PathwayStep6455 Recruitment of ZAP-70 to phosphorylated ITAMs Activation of ZAP-70 Phosphorylation of ZAP-70 by Lck Translocation of ZAP-70 to Immunological synapse Authored: Rudd, C.E., de Bono, B, Garapati, P V, 2008-01-24 15:53:10 Pubmed10375551 Reactome Database ID Release 43202430 Reactome, http://www.reactome.org ReactomeREACT_12596 Reviewed: Trowsdale, J, 2008-02-26 12:02:59 The dual phosphorylated ITAMs recruit Syk kinase ZAP-70 via their tandem SH2 domains (step 4). ZAP-70 subsequently undergoes phosphorylation on multiple tyrosine residues for further activation. ZAP-70 includes both positive and negative regulatory sites. Tyrosine 493 is a conserved regulatory site found within the activation loop of the kinase domain. This site has shown to be a positive regulatory site required for ZAP-70 kinase activity and is phosphorylated by Lck (step 5). This phosphorylation contributes to the active conformation of the catalytic domain. Later ZAP-70 undergoes trans-autophosphorylation at Y315 and Y319 (step 6). These sites appear to be positive regulatory sites. ZAP-70 achieves its full activation after the trans-autophosphorylation. Activated ZAP-70 along with Lck phosphorylates the multiple tyrosine residues in the adaptor protein LAT (step 7).