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(Received for publication, March 6, 1997)
From the Department of Pediatric Oncology, Dana-Farber Cancer
Institute and the Department of Pediatrics, Harvard Medical School,
Boston, Massachusetts 02115
Interleukin-2 (IL-2) activates the
receptor-associated Janus family tyrosine kinases, Jak1 and Jak3, which
in turn phosphorylate and activate specific STAT proteins (signal
transducers and activators of transcription), such as STAT5. Activation
of Jak and STAT proteins by IL-2 is transient and the mechanism for the
subsequent down-regulation of their activity is largely unknown. We
report here that IL-2-induced DNA-binding activity and tyrosine
phosphorylation of STAT5 are stabilized by a proteasome inhibitor
MG132; however, no detectable ubiquitination of the STAT proteins is
observed. This sustained STAT5 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 proteasome-mediated
protein degradation modulates protein-tyrosine phosphatase activity
that negatively regulates the Jak-STAT signaling pathways.
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