Involvement of Proteasomes in Regulating Jak-STAT Pathways upon Interleukin-2 Stimulation*
- From the Department of Pediatric Oncology, Dana-Farber Cancer Institute and the Department of Pediatrics, Harvard Medical School, Boston, Massachusetts 02115
Abstract
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.
Footnotes
-
↵* This work was supported by National Institutes of Health Grant AI-17258.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
-
↵‡ To whom correspondence should be addressed: Dept. of Pediatric Oncology, Dana-Farber Cancer Inst., 44 Binney St., Boston, MA 02115. Tel.: 617-632-3564; Fax: 617-632-4367; E-mail: steven_burakoff{at}dfci.harvard.edu.
-
↵1 The abbreviations used are: Jak, Janus kinase; STAT, signal transducer and activator of transcription; IFN-γ, interferon-γ; IL-2, interleukin-2; mAb, monoclonal antibody; EMSA, electrophoretic mobility shift assay; PBS, phosphate-buffered saline.
-
- Received March 6, 1997.
