PathwayStep6453 PathwayStep6452 PathwayStep6451 PathwayStep6450 PathwayStep6449 Inactivation of Lck by Csk Interaction of Csk with PAG Activation of Lck Dephosphorylation of Lck-pY505 by CD45 Phosphorylation of ITAM motifs in CD3 complexes Phosphorylation of CD3 and TCR zeta chains Authored: Rudd, C.E., de Bono, B, Garapati, P V, 2008-01-24 15:53:10 Prior to T cell receptor (TCR) stimulation, CD4/CD8 associated Lck remains seperated from the TCR and is maintained in an inactive state by the action of Csk. Csk phosphorylates the negative regulatory tyrosine of Lck and inactivates the Lck kinase domain. <p><br><br>Upon TCR stimulation, CD4/CD8 associated Lck co-localizes with the TCR leading to the phosphorylation of the CD3 and TCR subunit. Lck becomes activated by way of CD45-mediated dephosphorylation of negative regulatory tyrosine residues. The presence to PAG-bound Csk is further reduced via the dephosphorylation of PAG (step 1). <p><br><br>Lck is further activated by trans-autophosphorylation on the tyrosine residue on its activation loop (step 2). Active Lck further phosphorylates the tyrosine residues on CD3 chains. The signal-transducing CD3 delta/epsilon/gamma and TCR zeta chains contain a critical signaling motif known as the immunoreceptor tyrosine-based activation motif (ITAM). The two critical tyrosines of each ITAM motif are phosphorylated by Lck (step 3). Pubmed10375551 Reactome Database ID Release 43202427 Reactome, http://www.reactome.org ReactomeREACT_12582 Reviewed: Trowsdale, J, 2008-02-26 12:02:59