Suppressopm of growth of leukemia cells by a tyrosine kinase inhibitor JAB

在人类白血病中发现了12p13的TEL基因和9p24的JAK2酪氨酸激酶基因的融合。TEL介导的JAK2寡聚导致酪氨酸激酶(JH1)结构域的结构性激活，并使白介素3依赖的BA/F3细胞实现细胞因子无关的增殖。强制表达JAK抑制基因SOCS1/JAB/SSI-1诱导TEL-JAK2转化的BA/F3细胞凋亡。这种对TEL-JAK2活性的抑制依赖于SOCS盒介导的TEL-JAK2蛋白酶体的降解，而不是依赖于激酶抑制。JAK2的降解依赖于它的磷酸化，以及它通过激酶抑制区和SH2结构域与SOCS1的高亲和力结合。已证实von Hippel-Lindau病(VHL)抑癌基因产物具有SOCS盒，该盒与Elongin B、C和cullin-2形成复合体，并具有泛素连接酶的功能。SOCS1的SoCs盒也被证明与Elongins相互作用，但尚未证实泛素连接酶活性。我们发现SOCS盒与Cullin2相互作用，促进了TEL-JAK2的泛素化。此外，显性负向cullin 2的过表达抑制了SOCS1依赖的TEL-JAK2的降解。我们的研究证实了SOCS1对激活的JAK2具有底物特异性的E3泛素连接酶活性，并可能为抑制致癌酪氨酸激酶提供一种新的策略。

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 to 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, C and Cullin-2, and functions as an ubiquitin ligase.The SOCS box of SOCS1 has also been shown to interact with Elongins, however, ubiquitin ligase activity has not been demonstrated. We found that the SOCS box interacted with Cullin2 and promoted ubiquitination of TEL-JAK2.Furthermore, overexpression of dominant negative Cullin 2 suppressed SOCS1-dependent TEL-JAK2 degradation. Our study demonstrates 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.