c-Cbl inhibits angiogenesis and tumor growth by suppressing activation of PLCγ1
c-Cbl inhibits angiogenesis and tumor growth by suppressing activation of PLCγ1
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DOI：
10.1038/onc.2010.597
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发表时间：
2011-05-01
期刊：
影响因子：
8
通讯作者：
Rahimi, N.
中科院分区：
文献类型：
--
作者：
Meyer, R. D.;Husain, D.;Rahimi, N.
血管生成受具有促血管生成和抗血管生成功能的各种蛋白质的高度协调的功能调节。在由VEGFR-2激活的许多细胞质信号传导蛋白中，PLC γ 1的激活被认为在血管生成信号传导中具有关键作用。在以前的研究中，我们已经确定c-Cbl是内皮细胞中PLC γ 1的负调节因子，然而，c-Cbl在体内血管生成中的生化和生物学意义及其分子机制仍然是模糊的。在这项研究中，我们报告说，基因失活的c-Cbl在小鼠中的结果在增强肿瘤血管生成和视网膜新生血管。c-Cbl基因敲除小鼠的内皮细胞在VEGF刺激下表现出细胞增殖和管形成的升高。c-Cbl的丢失也导致PLC γ 1的强烈激活和细胞内钙释放增加。c-Cbl依赖的泛素化选择性地抑制PLC γ 1的酪氨酸磷酸化，并且主要抑制泛素介导的降解。因此，我们提出c-Cbl作为血管生成抑制蛋白，在激活后，它独特地通过泛素化调节PLC γ 1激活，随后抑制VEGF驱动的血管生成。Oncogene（2011）30，2198-2206; doi：10.1038/onc.2010.597; 2011年1月17日在线发表
Angiogenesis is regulated by highly coordinated function of various proteins with pro- and anti-angiogenic functions. Among the many cytoplasmic signaling proteins that are activated by VEGFR-2, activation of PLC gamma 1 is considered to have a pivotal role in angiogenic signaling. In previous study we have identified c-Cbl as a negative regulator of PLC gamma 1 in endothelial cells, the biochemical and biological significance of c-Cbl, however, in angiogenesis in vivo and molecular mechanisms involved were remained elusive. In this study, we report that genetic inactivation of c-Cbl in mice results in enhanced tumor angiogenesis and retinal neovascularization. Endothelial cells derived from c-Cbl null mice displayed elevated cell proliferation and tube formation in response to VEGF stimulation. Loss of c-Cbl also resulted in robust activation of PLC gamma 1 and increased intracellular calcium release. c-Cbl-dependent ubiquitination selectively inhibited tyrosine phosphorylation of PLC gamma 1 and mostly refrained from ubiquitin-mediated degradation. Hence, we propose c-Cbl as an angiogenic suppressor protein where upon activation it uniquely modulates PLC gamma 1 activation by ubiquitination and subsequently inhibits VEGF-driven angiogenesis. Oncogene (2011) 30, 2198-2206; doi:10.1038/onc.2010.597; published online 17 January 2011