Fes mediates the IL-4 activation of insulin receptor substrate-2 and cellular proliferation

Although Jak kinases are essential for initiating cytokine signaling, the r ole of other nonreceptor tyrosine kinases in this process remains unclear, We have examined the role of Fes in IL-4 signaling. Examination of Jak1-def icient cell lines demonstrates that Jak1 is required for the activation of Pes by IL-4, Experiments studying signaling molecules activated by IL-4 rec eptor suggest that IL-4 signaling can be subdivided into Pes-dependent and Fes-independent pathways. Overexpression of kinase-inactive Fes blocks the IL-4 activation of insulin receptor substrate-2, but not STAT6. Fes appears to be a downstream kinase from Jak1/Jak3 in this process. Further examinat ion of downstream signaling demonstrates that kinase-inactive Fes inhibits the recruitment of phosphoinositide 3-kinase to the activated IL-4 receptor complex and decreases the activation of p70(S6k) kinase in response to IL- 4, This inhibition correlates with a decrease in IL-4-induced proliferation . In contrast, mutant Fes does not inhibit the activation of Akt by IL-4, T hese data demonstrate that signaling pathways activated by IL-4 require dif ferent tyrosine kinases, This differential requirement predicts that specif ic kinase inhibitors may permit the disruption of specific IL-4-induced fun ctions.