Endothelial lumen signaling complexes control 3D matrix-specific tubulogenesis through interdependent Cdc42-and MT1-MMP-mediated events
Endothelial lumen signaling complexes control 3D matrix-specific tubulogenesis through interdependent Cdc42-and MT1-MMP-mediated events
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DOI：
10.1182/blood-2009-11-252692
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发表时间：
2010-06-24
期刊：
影响因子：
20.3
通讯作者：
Davis, George E.
中科院分区：
文献类型：
--
作者：
Sacharidou, Anastasia;Koh, Wonshill;Davis, George E.
在这里，我们定义了一个内皮细胞 (EC) 腔信号复合物，涉及 Cdc42、Par6b、Par3、连接粘附分子 (Jam)-B 和 Jam-C、膜型 1 基质金属蛋白酶 (MT1-MMP) 和整合素 α(2)β(1)，它们共同控制 3D 胶原基质中的人 EC 管生成。使用抗体、siRNA 或显性失活突变体阻断 Jam-B 和 Jam-C 会完全干扰由于缺乏 Cdc42 激活、抑制 Cdc42-GTP 依赖性信号转导和阻断 MT1-MMP 依赖性蛋白水解而导致的管腔和管形成。该过程需要相互依赖的 Cdc42 和 MT1-MMP 信号传导，其中涉及 Par3 与 Jam-B 和 Jam-C 细胞质尾部的结合，这是物理耦合管腔信号传导复合物组件所必需的相互作用。 MT1-MMP 蛋白水解活性对于 3D 胶原基质中 EC 管形成期间的 Cdc42 激活是必需的，但在 2D 胶原表面上则不然，而 Cdc42 激活对于 MT1-MMP 通过蛋白水解事件在 3D 基质中创建血管引导隧道和管网络是必需的。这项工作揭示了 Cdc42 依赖性信号传导和 MT1-MMP 依赖性蛋白水解的新的相互依赖作用，该过程选择性地发生在 3D 胶原基质中，并且需要 EC 腔信号复合物，以在血管形态发生过程中控制人类 EC 管状发生。 （血。2010；115（25）：5259-5269）
Here, we define an endothelial cell (EC) lumen signaling complex involving Cdc42, Par6b, Par3, junction adhesion molecule (Jam)-B and Jam-C, membrane type 1-matrix metalloproteinase (MT1-MMP), and integrin alpha(2)beta(1), which coassociate to control human EC tubulogenesis in 3D collagen matrices. Blockade of both Jam-B and Jam-C using antibodies, siRNA, or dominant-negative mutants completely interferes with lumen and tube formation resulting from a lack of Cdc42 activation, inhibition of Cdc42-GTP-dependent signal transduction, and blockade of MT1-MMP-dependent proteolysis. This process requires interdependent Cdc42 and MT1-MMP signaling, which involves Par3 binding to the Jam-B and Jam-C cytoplasmic tails, an interaction that is necessary to physically couple the components of the lumen signaling complex. MT1-MMP proteolytic activity is necessary for Cdc42 activation during EC tube formation in 3D collagen matrices but not on 2D collagen surfaces, whereas Cdc42 activation is necessary for MT1-MMP to create vascular guidance tunnels and tube networks in 3D matrices through proteolytic events. This work reveals a novel interdependent role for Cdc42-dependent signaling and MT1-MMP-dependent proteolysis, a process that occurs selectively in 3D collagen matrices and that requires EC lumen signaling complexes, to control human EC tubulogenesis during vascular morphogenesis. (Blood. 2010; 115(25):5259-5269)