Biomechanical insult switches PEA-15 activity to uncouple its anti-apoptotic function and promote erk mediated tissue remodeling
Biomechanical insult switches PEA-15 activity to uncouple its anti-apoptotic function and promote erk mediated tissue remodeling
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DOI：
10.1016/j.yexcr.2015.11.023
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发表时间：
2016-01-15
影响因子：
3.7
通讯作者：
Sivak, Jeremy M.
中科院分区：
文献类型：
--
作者：
Exler, Rachel E.;Guo, Xiaoxin;Sivak, Jeremy M.
生物力学损伤导致许多慢性病理过程，但对信号转导机制产生的影响却知之甚少。视网膜提供了一个极好的机械转导模型，因为视神经乳头 (ONH) 敏感星形胶质细胞的机械应变与基质金属蛋白酶 (MMP) 引起的慢性组织重塑和挖掘以及细胞凋亡密切相关。然而，生物力学应变引起这些效应的机制尚不清楚。我们之前通过对遭受病理相关生物力学损伤的人类 ONH 星形胶质细胞进行蛋白质组学分析，鉴定了小接头蛋白 PEA-15（星形胶质细胞中富集的磷蛋白）。在静息条件下，PEA-15 通过两个关键丝氨酸残基的磷酸化进行调节，以抑制外源性细胞凋亡和 ERK1/2 信号传导。然而，我们令人惊讶地观察到生物力学损伤显着改变 PEA-15 磷酸化和功能，从而解开其抗凋亡活性，并促进 ERK1/2 依赖性 MMP-2 和 MMP-9 分泌。这些结果揭示了一种新的细胞自主机制，生物力学应变通过该机制快速修改该信号通路以产生改变的组织损伤反应。 (C) 2015 Elsevier Inc. 保留所有权利。
Biomechanical insult contributes to many chronic pathological processes, yet the resulting influences on signal transduction mechanisms are poorly understood. The retina presents an excellent mechanotransduction model, as mechanical strain on sensitive astrocytes of the optic nerve head (ONH) is intimately linked to chronic tissue remodeling and excavation by matrix metalloproteinases (MMPs), and apoptotic cell death. However, the mechanism by which these effects are induced by biomechanical strain is unclear. We previously identified the small adapter protein, PEA-15 (phosphoprotein enriched in astrocytes), through proteomic analyses of human ONH astrocytes subjected to pathologically relevant biomechanical insult. Under resting conditions PEA-15 is regulated through phosphorylation of two key serine residues to inhibit extrinsic apoptosis and ERK1/2 signaling. However, we surprisingly observed that biomechanical insult dramatically switches PEA-15 phosphorylation and function to uncouple its anti-apoptotic activity, and promote ERK1/2-dependent MMP-2 and MMP-9 secretion. These results reveal a novel cell autonomous mechanism by which biomechanical strain rapidly modifies this signaling pathway to generate altered tissue injury responses. (C) 2015 Elsevier Inc. All rights reserved.