The SOCS box of SOCS-1 accelerates ubiquitin-dependent proteolysis of TEL-JAK2

Fusion of the TEL gene on 12p13 to the JAK2 tyrosine kinase gene on 9p24 ha s been found in human leukemia. TEL-mediated oligomerization of JAK2 result s in constitutive activation of the tyrosine kinase (JH1) domain and confer s cytokine-independent proliferation on interleukin-3-dependent Ba/F3 cells . Forced expression of the JAK inhibitor gene SOCS1/JAB/SSI-1 induced apopt osis of TEL-JAK2-transformed Ba/F3 cells, This suppression of TEL-JAK2 acti vity was dependent on SOCS box-mediated proteasomal degradation of TEL-JAK2 rather than on kinase inhibition. Degradation of JAK2 depended on its phos phorylation and its high affinity binding with SOCS1 through the kinase inh ibitory region and the SH2 domain. It has been demonstrated that von Hippel -Lindau disease (VHL) tumor-suppressor gene product possesses the SOCS box that forms a complex with Elongin B and C and Cullin-2, and it functions as a ubiquitin ligase. The SOCS box of SOCS1/JAB has also been shown to inter act with Elongins; however, ubiquitin ligase activity has not been demonstr ated. We found that the SOCS box interacted with Cullin-8 and promoted ubiq uitination of TEL-JAK2. Furthermore, overexpression of dominant negative Cu llin-2 suppressed SOCS1-dependent TEL-JAK2 degradation. Our study demonstra tes the substrate-specific E3 ubiquitinligase-like activity of SOCS1 for ac tivated JAK2 and may provide a novel strategy for the suppression of oncoge nic tyrosine kinases.