Stabilization of VEGFR2 signaling by cerebral cavernous malformation 3 is critical for vascular development.
Stabilization of VEGFR2 signaling by cerebral cavernous malformation 3 is critical for vascular development.
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DOI：
10.1126/scisignal.2000722
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发表时间：
2010-04-06
影响因子：
7.3
通讯作者：
Min W
中科院分区：
文献类型：
--
作者：
He Y;Zhang H;Yu L;Gunel M;Boggon TJ;Chen H;Min W
脑海绵状血管畸形（CCMs）是由三种功能未知的基因突变引起的人类血管畸形：CCM 1，CCM 2和CCM 3。CCM 3，也称为PDCD 10（程序性细胞死亡10），最初通过体外凋亡刺激对其mRNA的诱导来鉴定。然而，尚未确定CCM 3的体内功能。在这里，我们描述了CCM 3基因缺失的小鼠，无论是普遍存在的还是特定的某些细胞类型，包括血管内皮细胞，平滑肌细胞和神经元。具有CCM 3的全局或内皮细胞特异性缺失的小鼠在胚胎期死亡，表现出胚胎血管生成的缺陷。CCM 3缺失减少了胚胎和衍生内皮细胞中的VEGFR 2信号传导。响应于VEGF的刺激，CCM 3被募集到VEGFR 2并使其稳定，并且CCM 3的C末端结构域是VEGFR 2稳定所需的。事实上，在人类患者中发现的C-末端结构域缺失的CCM 3突变体是不稳定的，并且不能稳定和激活VEGFR 2。这些结果表明，CCM 3通过调节VEGFR 2信号传导来调节血管发育。
Cerebral cavernous malformations (CCMs) are human vascular malformations caused by mutations in three genes of unknown function: CCM1, CCM2, and CCM3. CCM3, also known as PDCD10 (programmed cell death 10), was initially identified by its mRNA induction by apoptotic stimuli in vitro. However, the in vivo function of CCM3 has not been determined. Here, we describe mice with a deletion of the CCM3 gene either ubiquitously or specifically in certain cell types, including the vascular endothelium, smooth muscle cells, and neurons. Mice with global or endothelial cell-specific deletion of CCM3 die at embryonic stage, exhibiting defects in embryonic angiogenesis. CCM3 deletion reduces VEGFR2 signaling in embryos and derived endothelial cells. CCM3 is recruited to and stabilizes VEGFR2 in response to stimulation by VEGF, and the C-terminal domain of CCM3 is required for the stabilization of VEGFR2. Indeed, the CCM3 mutants found in human patients with a deletion of the C-terminal domain were labile, and unable to stabilize and activate VEGFR2. These results demonstrate that CCM3 regulates vascular development by modulating VEGFR2 signaling.
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DOI：
10.1084/jem.20030077
发表时间：
2003-11-17
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Kano A;Wolfgang MJ;Gao Q;Jacoby J;Chai GX;Hansen W;Iwamoto Y;Pober JS;Flavell RA;Fu XY
通讯作者：
Fu XY
影响因子：
15.9
作者：
He, Yun;Luo, Yan;Min, Wang
通讯作者：
Min, Wang
影响因子：
3.5
作者：
Hogan, Benjamin M.;Bussmann, Jeroen;Schulte-Merker, Stefan
通讯作者：
Schulte-Merker, Stefan
影响因子：
4.8
作者：
Guclu, B;Ozturk, AK;Gunel, M
通讯作者：
Gunel, M
影响因子：
9.8
作者：
Denier, C;Goutagny, S;Tournier-Lasserve, E
通讯作者：
Tournier-Lasserve, E