INTERACTIONS BETWEEN THE TYROSINE KINASES P56LCK, P59FYN AND P50CSK IN CD4 SIGNALING IN T-CELLS

Interaction of the CD4 co-receptor with major histocompatibility compl ex (MHC) class II molecules during antigen presentation results in enh ancement of antigen receptor signaling. The synergism between the two receptors is believed to result from the juxtaposition of the CD4-asso ciated tyrosine kinase p56lck with the cytoplasmic domains of CD3 comp lex components. Here, we report that cross-linking of CD4 on the surfa ce of Jurkat cells using monoclonal antibodies results in activation o f the CD3-associated kinase p59fyn. Go-cross-linking of CD4 and CD3 re sults in synergistic activation of p59fyn. The p59fyn kinase is also h yperactive in a Jurkat cell line stably transfected with a constitutiv ely active p56lck mutant, indicating that p56lck mediates CD4 activati on of p59fyn. In support of this hypothesis, expression of a dominant inhibitory mutant of p59fyn blocks CD4 signals involved in gene activa tion. In addition, the p59fyn dominant inhibitor mutant blocks gene-ac tivating signals induced by expression of a constitutively active muta nt of p56lck. Overexpression of the regulatory kinase p50csk, which at tenuates TcR signaling by inactivation of p59fyn, inhibits signaling f rom the constitutively active form of p56lck. Taken together, these da ta suggest that CD4/p56lck enhancement of TcR signaling is, at least i n part, mediated by activation of p59fyn, and may be regulated by p50c sk.