TEC TYROSINE KINASE LINKS THE CYTOKINE RECEPTORS TO PI-3 KINASE PROBABLY THROUGH JAK

Tec/Btk tyrosine kinases are members of a subgroup of Src tyrosine kin ase family. They are reported to be activated in response to cytokines , such as IL-3 and IL-6. Janus kinases (JAKs) are known to associate w ith certain cytokine receptors, e.g. gp130, the signal transducing sub unit of IL-6 receptor, and the common beta chain of IL-3 receptor, whi ch can be activated upon receptor dimerization in response to cytokine s. Here we show the association between Jak1/Jak2 and Tec or Jak1 and Btk. Furthermore, Jak1 but not Jak2 induces tyrosine phosphorylation o f Btk, but not Tee. These observations suggest that upon cytokine stim ulation JAKs activate Tec/Btk or induce their dimerization resulting i n endogenous tyrosine phosphorylation. Furthermore using a yeast two-h ybrid system we have identified the target molecules for Tee, the p85 and p55PIK subunits of PI-3 kinase, and Vav. Tec associated with Vav t hrough its SH2 domain independently of its kinase activity. In contras t the p85 and p55PIK subunits of PI-3 kinase associated with the SH2-k inase domain of Tee, dependent on Tec kinase activity. Consistent with these, IL-6 or IL-3 induced the association between Tec and the p85 s ubunit of PI-3 kinase in mammalian cells. These findings suggest that Tec tyrosine kinase links cytokine receptors to PI-3 kinase probably t hrough JAKs.