A PINCH-1-Smurf1 signaling axis mediates mechano-regulation of BMPR2 and stem cell differentiation
A PINCH-1-Smurf1 signaling axis mediates mechano-regulation of BMPR2 and stem cell differentiation
复制标题
PINCH-1→Smurf1 信号轴介导 BMPR2 和干细胞分化的机械调节
DOI：
10.1083/jcb.201902022
复制
发表时间：
2019-11-01
影响因子：
7.8
通讯作者：
Wu, Chuanyue
中科院分区：
文献类型：
--
作者：
Guo, Ling;Wang, Rong;Wu, Chuanyue
力学环境在控制间充质干细胞(M5C)命运的过程中起着多重关键作用，但其潜在的信号机制尚不清楚。我们在这里报道了一个由Pinch-1、SMAD特异性E3泛素蛋白连接酶1(SMurf1)和骨形态发生蛋白2型受体(BMPR2)组成的信号轴，它将机械环境与MSC的命运决定联系起来。Pinch-1与SMurf1相互作用，从而抑制后者与BMPR2的相互作用，从而抑制BMPR2的降解，导致BMP信号增强和MSC成骨分化(OD)。细胞外基质(ECM)的硬化增加了Pinch-1的水平，从而激活了这个信号轴。PINCH-1的缺失阻断了刚性ECM诱导的BMP信号和OD，而过表达的PINCH-1则覆盖了来自软ECM的信号并促进了OD。最后，SMurf1或BMPR2表达的扰动足以阻断Pinch-1对BMP信号转导和MSC命运决定的影响。我们的发现揭示了机械环境控制BMPR2水平和MSC命运的关键信号机制。
Mechano-environment plays multiple critical roles in the control of mesenchymal stem cell (M5C) fate decision, but the underlying signaling mechanisms remain undefined. We report here a signaling axis consisting of PINCH-1, SMAD specific E3 ubiquitin protein ligase 1 (Smurf1), and bone morphogenetic protein type 2 receptor (BMPR2) that links mechano-environment to MSC fate decision. PINCH-1 interacts with Smurf1, which inhibits the latter from interacting with BMPR2 and consequently suppresses BMPR2 degradation, resulting in augmented BMP signaling and MSC osteogenic differentiation (OD). Extracellular matrix (ECM) stiffening increases PINCH-1 level and consequently activates this signaling axis. Depletion of PINCH-1 blocks stiff ECM-induced BMP signaling and OD, whereas overexpression of PINCH-1 overrides signals from soft ECM and promotes OD. Finally, perturbation of either Smurf1 or BMPR2 expression is sufficient to block the effects of PINCH-1 on BMP signaling and MSC fate decision. Our findings delineate a key signaling mechanism through which mechano-environment controls BMPR2 level and MSC fate decision.