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. PAG bound CSK phosphorylates the negative regulatory tyrosine of LCK and inactivates the LCK kinase domain (step 1). CSK also inhibits PTPN22 by sequestering it via binding (step 2).
Upon TCR stimulation, CSK dissociates from PAG1 (step 3) and PTPN22 (step4) and is unable to inhibit LCK. Furthermore, LCK becomes activated via PTPRC-mediated dephosphorylation of negative regulatory tyrosine residues (step 5). CD4/CD8 binds MHCII receptor in APC and the associated LCK co-localizes with the TCR.
LCK is further activated by trans-autophosphorylation on the tyrosine residue on its activation loop (step 6). 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 7).