Regulation of Jak2 through the ubiquitin-proteasome pathway involves phosphorylation of Jak2 on Y1007 and interaction with SOCS-1

Ungureanu, D; Saharinen, P; Junttila, I; Hilton, DJ; Silvennoinen, O

Author(s): Ungureanu, D; Saharinen, P; Junttila, I; Hilton, DJ; Silvennoinen, O;
Details: Publication Year 2002-05,Volume 22,Issue #10,Page 3316-3326
Journal Title: MOLECULAR AND CELLULAR BIOLOGY
Publication Type: Journal Article
Abstract: The family of cytoplasmic Janus (Jak) tyrosine kinases plays an essential role in cytokine signal transduction, regulating cell survival and gene expression. Ligand-induced receptor dimerization results in phosphorylation of Jak2 on activation loop tyrosine Y1007 and stimulation of its catalytic activity, which, in turn, results in activation of several downstream signaling cascades. Recently, the catalytic activity of Jak2 has been found to be subject to negative regulation through various mechanisms including association with SOCS proteins. Here we show that the ubiquitin-dependent proteolysis pathway is involved in the regulation of the turnover of activated Jak2. In unstimulated cells Jak2 was monoubiquitinated, and interleukin-3 or gamma interferon stimulation induced polyubiquitination of Jak2. The polyubiquitinated Jak2 was rapidly degraded through proteasomes. By using different Jak2 mutants we show that tyrosine-phosphorylated Jak2 is preferentially polyubiquitinated and degraded. Furthermore, phosphorylation of Y1007 on Jak2 was required for proteasomal degradation and for SOCS-1-mediated downregulation of Jak2. The proteasome inhibitor treatment stabilized the Jak2-SOCS-1 protein complex and inhibited the proteolysis of Jak2. In summary, these results indicate that the ubiquitin-proteasome pathway negatively regulates tyrosine-phosphorylated Jak2 in cytokine receptor signaling, which provides an additional mechanism to control activation of Jak2 and maintain cellular homeostasis.
Publisher: AMER SOC MICROBIOLOGY
Keywords: PROTEIN-TYROSINE-PHOSPHATASE; TUMOR-SUPPRESSOR PROTEIN; SIGNAL-TRANSDUCTION; CYTOKINE RECEPTORS; KINASE-ACTIVITY; ERYTHROPOIETIN RECEPTOR; MEDIATED DEGRADATION; ACTIVATION LOOP; SH2 DOMAIN; BOX MOTIF
Publisher's Version: https://doi.org/10.1128/MCB.22.10.3316-3326.2002
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2002-05-01 12:00:00