CCM3 signaling through sterile 20-like kinases plays an essential role during zebrafish cardiovascular development and cerebral cavernous malformations
CCM3 signaling through sterile 20-like kinases plays an essential role during zebrafish cardiovascular development and cerebral cavernous malformations
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DOI：
10.1172/jci39679
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发表时间：
2010-08-01
影响因子：
15.9
通讯作者：
Kahn, Mark L.
中科院分区：
文献类型：
--
作者：
Zheng, Xiangjian;Xu, Chong;Kahn, Mark L.
脑海绵状血管瘤是一种常见的人类血管疾病，是由于编码三种细胞内衔接蛋白脑海绵状血管瘤1蛋白（CCM1）、CCM2和CCM3的基因发生功能丧失突变而引起的。 CCM1、CCM2 和 CCM3 在小鼠和斑马鱼心血管发育过程中内皮细胞所需的通路中发生生化相互作用。该信号通路调节内皮功能的下游效应器尚未确定。在这里，我们在斑马鱼中证明，已知会导致人类脑海绵状血管瘤的突变 ccm3 蛋白 (ccm3 Delta) 的表达赋予与 ccm1 和 ccm2 缺失相关的心血管表型相同的心血管表型。 CCM3 Delta 蛋白与 CCM1 和 CCM2 相互作用，但不与已知结合野生型 CCM3、丝氨酸/苏氨酸蛋白激酶 MST4 (MST4)、无菌 20 样丝氨酸/苏氨酸激酶 24 (STK24) 和 STK25 的其他蛋白质相互作用，所有这些蛋白质的生物学功能均不明确。 CCM 缺陷的心血管表型特征是由于斑马鱼胚胎中 stk 缺陷以及 stks 和 ccm3 的低水平联合缺陷引起的。在培养的人内皮细胞中，CCM3和STK25以类似于CCM2的方式调节屏障功能，并且STK通过直接激活moesin负向调节Rho。这些研究将 STK 确定为发育和疾病过程中 CCM 信号传导的重要下游效应器，可调节内皮细胞和上皮细胞连接。
Cerebral cavernous malformation is a common human vascular disease that arises due to loss-of-function mutations in genes encoding three intracellular adaptor proteins, cerebral cavernous malformations 1 protein (CCM1), CCM2, and CCM3. CCM1, CCM2, and CCM3 interact biochemically in a pathway required in endothelial cells during cardiovascular development in mice and zebrafish. The downstream effectors by which this signaling pathway regulates endothelial function have not yet been identified. Here we have shown in zebrafish that expression of mutant ccm3 proteins (ccm3 Delta) known to cause cerebral cavernous malformation in humans confers cardiovascular phenotypes identical to those associated with loss of ccm1 and ccm2. CCM3 Delta proteins interacted with CCM1 and CCM2, but not with other proteins known to bind wild-type CCM3, serine/threonine protein kinase MST4 (MST4), sterile 20-like serine/threonine kinase 24 (STK24), and STK25, all of which have poorly defined biological functions. Cardiovascular phenotypes characteristic of CCM deficiency arose due to stk deficiency and combined low-level deficiency of stks and ccm3 in zebrafish embryos. In cultured human endothelial cells, CCM3 and STK25 regulated barrier function in a manner similar to CCM2, and STKs negatively regulated Rho by directly activating moesin. These studies identify STKs as essential downstream effectors of CCM signaling in development and disease that may regulate both endothelial and epithelial cell junctions.