Restriction of Src activity by Cullin-5.
Restriction of Src activity by Cullin-5.
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DOI：
10.1016/j.cub.2008.12.007
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发表时间：
2009-01-27
期刊：
影响因子：
--
通讯作者：
Cooper JA
中科院分区：
文献类型：
--
作者：
Laszlo GS;Cooper JA
Src是一种非受体酪氨酸激酶，可协调多种可溶性和粘附性信号分子的反应，并调节细胞增殖、存活、分化和迁移。通常，Src活性受到严格调节，并且Src催化的磷酸化被磷酸酪氨酸磷酸酶平衡。然而，失调突变Src导致恶性转化时，高度表达。Src转化是剂量依赖性的，但目前还不清楚与内源性Src相比，转化需要多少突变体Src。在这里，我们表明，转化需要高水平的突变体src mRNA的过表达，部分原因是活性Src蛋白被泛素介导的蛋白水解降解。我们发现，活性，但不是无活性的Src蛋白下调，这取决于假定的肿瘤抑制因子和E3泛素连接酶的组成部分，Cullin-5（Cul 5）。Cul 5去除协同与突变src mRNA的生理水平，以增加蛋白质酪氨酸磷酸化，诱导形态转化，并解除生长调节。Cul 5还抑制Src诱导的肿瘤发生并调节正常细胞中的Src信号传导。这些结果表明，当Src被激活的突变或生理机制，其影响是有限的Cul 5，下调活性Src及其磷酸化底物。这些发现证明了下调细胞中Src信号的新机制的重要性。
Src is a nonreceptor tyrosine kinase that coordinates responses to diverse soluble and adhesive signaling molecules and regulates cell proliferation, survival, differentiation and migration. Normally, Src activity is tightly regulated, and Src-catalyzed phosphorylation is counterbalanced by phosphotyrosine phosphatases. However, deregulated mutant Src causes malignant transformation when highly expressed. Src transformation is dose dependent, but it has been unclear how much mutant Src, compared with endogenous Src, is required for transformation. Here, we show that transformation requires highlevel overexpression of mutant src mRNA, in part because active Src protein is degraded by ubiquitin-mediated proteolysis. We show that active but not inactive Src protein is downregulated depending on the putative tumor suppressor and E3 ubiquitin ligase component, Cullin-5 (Cul5). Cul5 removal synergizes with physiological levels of mutant src mRNA to increase protein tyrosine phosphorylation, induce morphological transformation, and deregulate growth. Cul5 also represses Src-induced tumorigenesis and regulates Src signaling in normal cells. These results suggest that, when Src is activated by mutation or physiological mechanisms, its effects are limited by Cul5, which downregulates active Src and its phosphorylated substrates. These findings demonstrate the importance of a new mechanism that downregulates Src signaling in cells.
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影响因子：
37.3
作者：
Fay MJ;Longo KA;Karathanasis GA;Shope DM;Mandernach CJ;Leong JR;Hicks A;Pherson K;Husain A
通讯作者：
Husain A
影响因子：
56.9
作者：
FINNEY, RE;BISHOP, JM
通讯作者：
BISHOP, JM
影响因子：
8
作者：
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通讯作者：
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影响因子：
64.5
作者：
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通讯作者：
SORIANO, P
影响因子：
64.8
作者：
COHEN, JB;LEVINSON, AD
通讯作者：
LEVINSON, AD