INVOLVEMENT OF PROTEASOMES IN REGULATING JAK-STAT PATHWAYS UPON INTERLEUKIN-2 STIMULATION

Interleukin-2 (IL-2) activates the receptor-associated Janus family ty rosine kinases, Jak1 and Jak3, which in turn phosphorylate and activat e specific STAT proteins (signal transducers and activators of transcr iption), such as STATE. Activation of Jak and STAT proteins by IL-2 is transient and the mechanism for the subsequent down-regulation of the ir activity is largely unknown. We report here that IL-2-induced DNA-b inding activity and tyrosine phosphorylation of STATE are stabilized b y a proteasome inhibitor MG132; however, no detectable ubiquitination of the STAT proteins is observed. This sustained STATE activation can be blocked by protein kinase inhibitors, which is consistent with the ability of the proteasome inhibitor to stabilize IL-2-induced tyrosine phosphorylation of Jak1 and Jak3. These results suggest that proteaso me-mediated protein degradation modulates protein-tyrosine phosphatase activity that negatively regulates the Jak-STAT signaling pathways.