BAZF, a novel component of cullin3-based E3 ligase complex, mediates VEGFR and Notch cross-signaling in angiogenesis
BAZF, a novel component of cullin3-based E3 ligase complex, mediates VEGFR and Notch cross-signaling in angiogenesis
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DOI：
10.1182/blood-2011-03-345306
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发表时间：
2012-03-15
期刊：
影响因子：
20.3
通讯作者：
Higashiyama, Shigeki
中科院分区：
文献类型：
--
作者：
Ohnuki, Hidetaka;Inoue, Hirofumi;Higashiyama, Shigeki
血管生成稳态是由血管内皮生长因子（VEGF）和内皮细胞（ECs） Notch信号之间的平衡维持的。我们筛选了可能介导VEGF信号转导与Notch信号下调耦合的分子，并鉴定了b细胞慢性淋巴细胞白血病/淋巴瘤6相关锌指蛋白（BAZF）。在ECs中，VEGF-A诱导BAZF与Notch信号因子Cpromoter binding factor 1 （CBF1）结合，并通过CBF1-cullin3 (CUL3) E3连接酶复合物的多泛素化促进CBF1的降解。体内BAZF的破坏减少了内皮尖端细胞的数量和丝状足的突出，并显著消除了小鼠视网膜血管丛的形成，重叠了Notch激活后的视网膜表型。此外，在皮肤损伤的BAZF（-/-）小鼠中观察到血管生成和毛细血管重塑受损。因此，我们提出BAZF通过基于BAZF- cul3的多泛素化依赖性CBF1降解来下调Notch信号来支持血管生成发芽。(119年血。2012;(11):2688 - 2698)
Angiogenic homeostasis is maintained by a balance between vascular endothelial growth factor (VEGF) and Notch signaling in endothelial cells (ECs). We screened for molecules that might mediate the coupling of VEGF signal transduction with down-regulation of Notch signaling, and identified B-cell chronic lymphocytic leukemia/lymphoma6-associated zinc finger protein (BAZF). BAZF was induced by VEGF-A in ECs to bind to the Notch signaling factor Cpromoter binding factor 1 (CBF1), and to promote the degradation of CBF1 through polyubiquitination in a CBF1-cullin3 (CUL3) E3 ligase complex. BAZF disruption in vivo decreased endothelial tip cell number and filopodia protrusion, and markedly abrogated vascular plexus formation in the mouse retina, over-lapping the retinal phenotype seen in response to Notch activation. Further, impaired angiogenesis and capillary remodeling were observed in skin-wounded BAZF(-/-) mice. We therefore propose that BAZF supports angiogenic sprouting via BAZF-CUL3-based polyubiquitination-dependent degradation of CBF1 to down-regulate Notch signaling. (Blood. 2012;119(11):2688-2698)