Src phosphorylation converts Mdm2 from a ubiquitinating to a neddylating E3 ligase
Src phosphorylation converts Mdm2 from a ubiquitinating to a neddylating E3 ligase
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DOI：
10.1073/pnas.1416656112
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发表时间：
2015-02-10
影响因子：
11.1
通讯作者：
Mayo, Lindsey D.
中科院分区：
文献类型：
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作者：
Batuello, Christopher N.;Hauck, Paula M.;Mayo, Lindsey D.
小鼠双分钟2蛋白(MDM2)是一种多方面的磷酸化蛋白，参与调节多种蛋白的表达，其中包括肿瘤抑制蛋白P53。MDM2结合并参与泛素或Nedd8(神经前体细胞表达，发育下调的8)与P53的结合。虽然对MDM2的E3泛素活性的调节已被研究，但对MDM2的调节活性仍有待确定。在这里，我们证明了激活的c-Src激酶使MDM2的Y281和Y302磷酸化，导致MDM2的稳定性增加，并与尿毒复合体的E2酶Ubc12相关联。依赖于MDM2的P53的Nedd8结合导致转录失活的P53，这一过程被小分子抑制剂逆转为Src或Ubc12。因此，我们的研究揭示了MDM2如何中和和上调活跃增殖细胞中的P53，并为在野生型P53肿瘤中使用针对Nedd8途径的治疗提供了理论基础。
Murine double minute-2 protein (Mdm2) is a multifaceted phosphorylated protein that plays a role in regulating numerous proteins including the tumor suppressor protein p53. Mdm2 binds to and is involved in conjugating either ubiquitin or Nedd8 (Neural precursor cell expressed, developmentally down-regulated 8) to p53. Although regulation of the E3 ubiquitin activity of Mdm2 has been investigated, regulation of the neddylating activity of Mdm2 remains to be defined. Here we show that activated c-Src kinase phosphorylates Y281 and Y302 of Mdm2, resulting in an increase in Mdm2 stability and its association with Ubc12, the E2 enzyme of the neddylating complex. Mdm2-dependent Nedd8 conjugation of p53 results in transcriptionally inactive p53, a process that is reversed with a small molecule inhibitor to either Src or Ubc12. Thus, our studies reveal how Mdm2 may neutralize and elevate p53 in actively proliferating cells and also provides a rationale for using therapies that target the Nedd8 pathway in wild-type p53 tumors.