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窖蛋白-1 通过肌动蛋白依赖性的 YAP 调控调节细胞对基质硬度的力学转导反应。

Caveolin-1 Modulates Mechanotransduction Responses to Substrate Stiffness through Actin-Dependent Control of YAP.

机构信息

Mechanoadaptation & Caveolae Biology Lab, Cell and Developmental Biology Area, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid 28029, Spain.

Cardiovascular Proteomics Unit, CNIC, Madrid 28029, Spain.

出版信息

Cell Rep. 2018 Nov 6;25(6):1622-1635.e6. doi: 10.1016/j.celrep.2018.10.024.

DOI:10.1016/j.celrep.2018.10.024
PMID:30404014
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6231326/
Abstract

The transcriptional regulator YAP orchestrates many cellular functions, including tissue homeostasis, organ growth control, and tumorigenesis. Mechanical stimuli are a key input to YAP activity, but the mechanisms controlling this regulation remain largely uncharacterized. We show that CAV1 positively modulates the YAP mechanoresponse to substrate stiffness through actin-cytoskeleton-dependent and Hippo-kinase-independent mechanisms. RHO activity is necessary, but not sufficient, for CAV1-dependent mechanoregulation of YAP activity. Systematic quantitative interactomic studies and image-based small interfering RNA (siRNA) screens provide evidence that this actin-dependent regulation is determined by YAP interaction with the 14-3-3 protein YWHAH. Constitutive YAP activation rescued phenotypes associated with CAV1 loss, including defective extracellular matrix (ECM) remodeling. CAV1-mediated control of YAP activity was validated in vivo in a model of pancreatitis-driven acinar-to-ductal metaplasia. We propose that this CAV1-YAP mechanotransduction system controls a significant share of cell programs linked to these two pivotal regulators, with potentially broad physiological and pathological implications.

摘要

转录调节因子 YAP 协调许多细胞功能，包括组织稳态、器官生长控制和肿瘤发生。机械刺激是 YAP 活性的一个关键输入，但控制这种调节的机制在很大程度上仍未被描述。我们表明 CAV1 通过肌动球蛋白细胞骨架依赖性和 Hippo 激酶非依赖性机制正向调节 YAP 对基质硬度的机械反应。RHO 活性对于 CAV1 依赖的 YAP 活性的机械调节是必要的，但不是充分的。系统的定量相互作用组学研究和基于图像的小干扰 RNA (siRNA) 筛选提供了证据，表明这种肌动球蛋白依赖性调节是由 YAP 与 14-3-3 蛋白 YWHAH 的相互作用决定的。组成型 YAP 激活挽救了与 CAV1 缺失相关的表型，包括细胞外基质 (ECM) 重塑缺陷。在胰腺炎驱动的腺泡到导管化生模型中，体内验证了 CAV1 介导的 YAP 活性控制。我们提出，这种 CAV1-YAP 机械转导系统控制与这两个关键调节剂相关的大量细胞程序，具有潜在的广泛的生理和病理意义。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3d67/6231326/9517856c2094/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3d67/6231326/d6de7765ef79/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3d67/6231326/eab8677d8ada/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3d67/6231326/18109eef4886/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3d67/6231326/46904a67d045/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3d67/6231326/ff1c04cc67ea/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3d67/6231326/6c33a0f1eb66/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3d67/6231326/9517856c2094/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3d67/6231326/d6de7765ef79/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3d67/6231326/eab8677d8ada/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3d67/6231326/18109eef4886/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3d67/6231326/46904a67d045/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3d67/6231326/ff1c04cc67ea/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3d67/6231326/6c33a0f1eb66/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3d67/6231326/9517856c2094/gr6.jpg

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