Differential T-cell antigen receptor signaling mediated by the Src family kinases Lck and Fyn

Src family tyrosine kinases play a key role in T-cell antigen receptor (TCR ) signaling. They are responsible for the initial tyrosine phosphorylation of the receptor, leading to the recruitment of the ZAP-70 tyrosine kinase, as well as the subsequent phosphorylation and activation of ZAP-70. Molecul ar and genetic evidence indicates that both the Fyn and Lck members of the Src family can participate in TCR signal transduction; however, it is uncle ar to what extent they utilize the same signal transduction pathways and ac tivate the same downstream events. We have addressed this issue by examinin g the ability of Fyn to mediate TCR signal transduction in an Lck-deficient T-cell line (JCaM1). Fyn was able to induce tyrosine phosphorylation of th e TCR and recruitment of the ZAP-70 kinase, but the pattern of TCR phosphor ylation was altered and activation of ZAP-70 was defective. Despite this, t he SLP-76 adapter protein aas inducibly tyrosine phosphorylated, and both t he Ras-mitogen-activated protein kinase and the phosphatidylinositol 4,5-bi phosphate signaling pathways were activated. TCR stimulation of JCaM1/Fyn c ells induced the expression of the CD69 activation marker and inhibited cel l growth, but NFAT activation and the production of interleukin-a were mark edly reduced. These results indicate that Fyn mediates an alternative form of TCR signaling which is independent of ZAP-70 activation and generates a distinct cellular phenotype. Furthermore, these findings imply that the out come of TCR signal transduction may be determined by which Src family kinas e is used to initiate signaling.