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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 has been found in human leukemia. TEL-mediated oligomerization of JAK2 results in constitutive activation of the tyrosine kinase (JH1) domain and confers cytokine-independent proliferation on interleukin-3-dependent Ba/F3 cells. Forced expression of the JAK inhibitor gene SOCS1/JAB/SSI-1 induced apoptosis of TEL-JAK2-transformed Ba/F3 cells. This suppression of TEL-JAK2 activity was dependent on SOCS box-mediated proteasomal degradation of TEL-JAK2 rather than on kinase inhibition. Degradation of JAK2 depended on its phosphorylation and its high affinity binding with SOCS1 through the kinase inhibitory 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 interact with Elongins; however, ubiquitin ligase activity has not been demonstrated. We found that the SOCS box interacted with Cullin-2 and promoted ubiquitination of TEL-JAK2. Furthermore, overexpression of dominant negative Cullin-2 suppressed SOCS1-dependent TEL-JAK2 degradation. Our study demonstrates the substrate-specific E3 ubiquitin-ligase-like activity of SOCS1 for activated JAK2 and may provide a novel strategy for the suppression of oncogenic tyrosine kinases.

Pubmed ID: 11278610 RIS Download

Mesh terms: Animals | Binding Sites | Carrier Proteins | Cell Cycle Proteins | Cell Division | Cell Line | Chromosomes, Human, Pair 12 | Chromosomes, Human, Pair 9 | Cullin Proteins | Humans | Intracellular Signaling Peptides and Proteins | Kinetics | Leukemia | Mice | Mutagenesis | Oncogene Proteins, Fusion | Phosphorylation | Recombinant Fusion Proteins | Recombinant Proteins | Repressor Proteins | Suppressor of Cytokine Signaling 1 Protein | Suppressor of Cytokine Signaling Proteins | Transcription Factors | Transfection | Ubiquitins | src Homology Domains