Speculative model for reciprocal regulation of tyrosine phosphorylation in lymphocytes. We hypothesize that Lck traffics between rafts and other subcellular pools based upon its tyrosine phosphorylation status. (a) Thus, in the resting T cell, Lck is in a dynamic equilibrium between its inactive and primed conformations due to the reciprocal activity of the phosphatase CD45RA+ and the kinase Csk/PEP. (b) Upon T cell activation, rafts coalesce and an immunological synapse forms. CD45RA+ is excluded from the immunological synapse due to its size. PAG is dephosphorylated by an unknown phosphatase, resulting in release of Csk/PEP. Unopposed, primed Lck is thus able to undergo transphosphorylation at Y394, which yields an active kinase that subsequently phosphorylates the ITAMs of the CD3 and ζ chains. The phosphorylated ITAMs provide docking sites for the SH2 domains of ZAP-70. ZAP-70 is further phosphorylated by Lck, and activation of downstream signaling events ensues. (c) During downregulation, the CD45RO isoform is inactivated by homodimerization. PAG is again phosphorylated, recruiting Csk/PEP to the raft, where Lck becomes phosphorylated at Y505 and dephosphorylated at Y394, leaving this kinase in an inactive conformation.