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)

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CD3D , CD3E , CD3G , CD247 , CD4 , HLA-DPA1 , HLA-DPB1 , HLA-DQA1 , HLA-DQA2 , HLA-DQB1 , HLA-DQB2 , HLA-DRA , HLA-DRB1 , HLA-DRB5 , LCK , ZAP70 , PTPN22 , TRAC ,