Hierarchy of protein tyrosine kinases in interleukin-2 (IL2) signaling: Activation of Syk depends on Jak3; However, neither Syk nor Lck is required for IL-2-mediated STAT activation

Interleukin-2 (IL-2) activates several different families of tyrosine kinas es, but precisely how these kinases interact is not completely understood. We therefore investigated the functional relationships among Jak3, Lck, and Syk in IL-2 signaling. We first observed that in the absence of Jak3, both Lck and Syk had the capacity to phosphorylate Stat3 and Stat5a. However, n either supported IL-2-induced STAT activation, nor did dominant negative al leles of these kinases inhibit. Moreover, pharmacological abrogation of Lck activity did not inhibit IL-2-mediated phosphorylation of Jak3 acid Stat5a . Importantly, ligand-dependent Syk activation was dependent on the presenc e of catalytically active Jak3, whereas Lck activation was not. Interesting ly, Syk functioned as a direct substrate of Jak1 but not Jak3. Additionally , Jak3 phosphorylated Jak1, whereas the reverse was not the case. Taken tog ether, our data support a model in which Lck functions in parallel with Jak 3, while Syk functions as a downstream element of Jak3 in IL-2 signaling. J ak3 may regulate Syk catalytic activity indirectly via Jak1. However, IL-2- mediated Jak3/Stat activation is not dependent on Lck or Syk. While the ess ential roles of Jak1 and Jak3 in signaling by gamma c-utilizing cytokines a re clear, it will be important to dissect the exact contributions of Lck an d Syk in mediating the effects of IL-2 and related cytokines.