Transglutaminase 2 as a novel activator of LRP6/β-catenin signaling
Transglutaminase 2 as a novel activator of LRP6/β-catenin signaling
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DOI：
10.1016/j.cellsig.2013.08.016
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发表时间：
2013-12-01
影响因子：
4.8
通讯作者：
Nurminskaya, M.
中科院分区：
文献类型：
--
作者：
Deasey, S.;Nurminsky, D.;Nurminskaya, M.
-连环蛋白信号轴对成人正常胚胎发育和组织稳态至关重要。我们之前已经证明细胞外酶转谷氨酰胺酶2 （TG2）激活血管平滑肌细胞（VSMCs）中的β -连环蛋白信号。在这项研究中，我们提供了几条证据，证明TG2作为LRP5/6受体的激活配体起作用。具体来说，我们发现TG2与LRP6协同激活Cos-7细胞中β -连环蛋白依赖基因的表达。干扰LRP5/6受体可减弱Cos-7细胞中tg2诱导的β -连环蛋白激活。此外，我们发现TG2直接结合到LRP6的细胞外结构域，LRP6也能够作为TG2介导的蛋白交联的底物。此外，TG2蛋白交联抑制剂抑制了TG2诱导的β -连环蛋白激活，暗示蛋白交联是该途径的一种新的调控机制。总之，我们的研究结果确定并表征了LRP5/6受体的新激活配体，并揭示了TG2作为β -连环蛋白信号激动剂的新活性，有助于理解转谷氨酰胺酶和β -连环蛋白信号相关的多种发育事件和病理条件。(C) 2013爱思唯尔公司版权所有。
The beta-catenin signaling axis is critical for normal embryonic development and tissue homeostasis in adults. We have previously shown that extracellular enzyme transglutaminase 2 (TG2) activates beta-catenin signaling in vascular smooth muscle cells (VSMCs). In this study, we provide several lines of evidence that TG2 functions as an activating ligand of the LRP5/6 receptors. Specifically, we show that TG2 synergizes with LRP6 in the activation of beta-catenin-dependent gene expression in Cos-7 cells. Interfering with the LRP5/6 receptors attenuates TG2-induced activation of beta-catenin in Cos-7 cells. Further, we show that TG2 binds directly to the extracellular domain of LRP6, which is also able to act as a substrate for TG2-mediated protein cross-linking. Furthermore, inhibitors of TG2 protein cross-linking quench the observed TG2-induced beta-catenin activation, implicating protein cross-linking as a novel regulatory mechanism for this pathway. Together, our findings identify and characterize a new activating ligand of the LRP5/6 receptors and uncover a novel activity of TG2 as an agonist of beta-catenin signaling, contributing to the understanding of diverse developmental events and pathological conditions in which transglutaminase and beta-catenin signaling are implicated. (C) 2013 Elsevier Inc. All rights reserved.