Obligatory cross-talk with the tyrosine kinases assembled with the TCR/CD3complex in CD4 signal transduction

Dissection of the CD4 signal transduction pathway has revealed striking sim ilarities with the TCR/CD3 pathway. Furthermore, downstream signaling by CD 4 is impaired in cells lacking surface TCR, suggesting a role for the TCR/C D3 complex in CD4 signal transduction. We have investigated the molecular b asis for the dependence of CD4 signaling on TCR/CD3 expression. Using the p hosphotyrosine binding domains of the Shc adaptor and the Fyn kinase, which both participate in CD4 signaling, as baits, we show that CD4 induces tyro sine phosphorylation of a subset of the proteins phosphorylated in response to TCR/CD3 engagement. The phosphoprotein patterns were dramatically alter ed in cells defective for TCR/CD3 expression, and were recoverable by recon stitution of correctly assembled TCR, suggesting that CD4 uses TCR/CD3-asso ciated tyrosine kinases to signal. Among the tyrosine kinases associated wi th the resting TCR/CD3 complex, only Fyn is activated following CD4 engagem ent. The failure of Fyn to become phosphorylated in cells defective for TCR expression underlines the unique role of TCR/CD3 associated Fyn in CD4 sig nal transduction. While no calcium mobilization was measurable in cells def ective for TCR/CD3 expression in response to CD4 engagement, the Ras/MAP ki nase pathway could be partially activated. Thus, CD4 activates at least two signaling pathways, and tyrosine kinases associated with the TCR/CD3 compl ex are key components of one of these pathways.