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

Cell reports | 2018

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.

Pubmed ID: 30404014 RIS Download

Research resources used in this publication

Associated grants

  • Agency: Worldwide Cancer Research, United Kingdom
    Id: 15-0404

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This is a list of tools and resources that we have found mentioned in this publication.


Enrichr (tool)

RRID:SCR_001575

A web-based gene list enrichment analysis tool that provides various types of visualization summaries of collective functions of gene lists. It includes new gene-set libraries, an alternative approach to rank enriched terms, and various interactive visualization approaches to display enrichment results using the JavaScript library, Data Driven Documents (D3). The software can also be embedded into any tool that performs gene list analysis. System-wide profiling of genes and proteins in mammalian cells produce lists of differentially expressed genes / proteins that need to be further analyzed for their collective functions in order to extract new knowledge. Once unbiased lists of genes or proteins are generated from such experiments, these lists are used as input for computing enrichment with existing lists created from prior knowledge organized into gene-set libraries.

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Addgene (tool)

RRID:SCR_002037

Non-profit plasmid repository dedicated to helping scientists around the world share high-quality plasmids. Facilitates archiving and distributing DNA-based research reagents and associated data to scientists worldwide. Repository contains over 65,000 plasmids, including special collections on CRISPR, fluorescent proteins, and ready-to-use viral preparations. There is no cost for scientists to deposit plasmids, which saves time and money associated with shipping plasmids themselves. All plasmids are fully sequenced for validation and sequencing data is openly available. We handle the appropriate Material Transfer Agreements (MTA) with institutions, facilitating open exchange and offering intellectual property and liability protection for depositing scientists. Furthermore, we curate free educational resources for the scientific community including a blog, eBooks, video protocols, and detailed molecular biology resources.

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GraphPad Prism (tool)

RRID:SCR_002798

Statistical analysis software that combines scientific graphing, comprehensive curve fitting (nonlinear regression), understandable statistics, and data organization. Designed for biological research applications in pharmacology, physiology, and other biological fields for data analysis, hypothesis testing, and modeling.

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QIAGEN (tool)

RRID:SCR_008539

A commercial organization which provides assay technologies to isolate DNA, RNA, and proteins from any biological sample. Assay technologies are then used to make specific target biomolecules, such as the DNA of a specific virus, visible for subsequent analysis.

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Ingenuity Pathway Analysis (tool)

RRID:SCR_008653

A web-based software application that enables users to analyze, integrate, and understand data derived from gene expression, microRNA, and SNP microarrays, metabolomics, proteomics, and RNA-Seq experiments, and small-scale experiments that generate gene and chemical lists. Users can search for targeted information on genes, proteins, chemicals, and drugs, and build interactive models of experimental systems. IPA allows exploration of molecular, chemical, gene, protein and miRNA interactions, creation of custom molecular pathways, and the ability to view and modify metabolic, signaling, and toxicological canonical pathways. In addition to the networks and pathways that can be created, IPA can provide multiple layering of additional information, such as drugs, disease genes, expression data, cellular functions and processes, or a researchers own genes or chemicals of interest.

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ATCC (tool)

RRID:SCR_001672

Global nonprofit biological resource center (BRC) and research organization that provides biological products, technical services and educational programs to private industry, government and academic organizations. Its mission is to acquire, authenticate, preserve, develop and distribute biological materials, information, technology, intellectual property and standards for the advancement and application of scientific knowledge. The primary purpose of ATCC is to use its resources and experience as a BRC to become the world leader in standard biological reference materials management, intellectual property resource management and translational research as applied to biomaterial development, standardization and certification. ATCC characterizes cell lines, bacteria, viruses, fungi and protozoa, as well as develops and evaluates assays and techniques for validating research resources and preserving and distributing biological materials to the public and private sector research communities.

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Promega (tool)

RRID:SCR_006724

An Antibody supplier

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Millipore (tool)

RRID:SCR_008983

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KEGG (tool)

RRID:SCR_012773

Integrated database resource consisting of 16 main databases, broadly categorized into systems information, genomic information, and chemical information. In particular, gene catalogs in completely sequenced genomes are linked to higher-level systemic functions of cell, organism, and ecosystem. Analysis tools are also available. KEGG may be used as reference knowledge base for biological interpretation of large-scale datasets generated by sequencing and other high-throughput experimental technologies.

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C57BL/6J (tool)

RRID:IMSR_JAX:000664

Mus musculus with name C57BL/6J from IMSR.

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TEF-1 (H-4) (antibody)

RRID:AB_10988229

This monoclonal targets TEF-1 (H-4)

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H3-celegans (antibody)

RRID:AB_302613

This polyclonal targets H3

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YAP (D8H1X) XP Rabbit mAb (antibody)

RRID:AB_2650491

This recombinant monoclonal targets YAP

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Rho GDIalpha (A-20) (antibody)

RRID:AB_2227516

This polyclonal targets ARHGDIA

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Caveolin-1 (D46G3) XP Rabbit mAb (antibody)

RRID:AB_2275453

This monoclonal targets Caveolin-1

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14-3-3 η (D23B7) Rabbit mAb (antibody)

RRID:AB_10829034

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Goat anti-Mouse IgG (H+L) Secondary Antibody, HRP (antibody)

RRID:AB_228307

This polyclonal secondary targets IgG (H+L)

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LATS1 Antibody (antibody)

RRID:AB_2296754

This polyclonal targets LATS1

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YAP (63.7) (antibody)

RRID:AB_1131430

This monoclonal targets YAP (63.7)

View all literature mentions

HeLa (cell line)

RRID:CVCL_0030

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View all literature mentions

MDA-MB-231 (cell line)

RRID:CVCL_0062

Cell line MDA-MB-231 is a Cancer cell line with a species of origin Homo sapiens (Human)

View all literature mentions

MDA-MB-231 (cell line)

RRID:CVCL_0062

Cell line MDA-MB-231 is a Cancer cell line with a species of origin Homo sapiens (Human)

View all literature mentions

HeLa (cell line)

RRID:CVCL_0030

Cell line HeLa is a Cancer cell line with a species of origin Homo sapiens

View all literature mentions

Goat anti-Mouse IgG (H+L) Secondary Antibody, HRP (antibody)

RRID:AB_228307

This polyclonal secondary targets IgG (H+L)

View all literature mentions

YAP (D8H1X) XP Rabbit mAb (antibody)

RRID:AB_2650491

This recombinant monoclonal targets YAP

View all literature mentions

Rho GDIalpha (A-20) (antibody)

RRID:AB_2227516

This polyclonal targets ARHGDIA

View all literature mentions

LATS1 Antibody (antibody)

RRID:AB_2296754

This polyclonal targets LATS1

View all literature mentions

14-3-3 η (D23B7) Rabbit mAb (antibody)

RRID:AB_10829034

This monoclonal targets 14-3-3 η

View all literature mentions

H3-celegans (antibody)

RRID:AB_302613

This polyclonal targets H3

View all literature mentions

TEF-1 (H-4) (antibody)

RRID:AB_10988229

This monoclonal targets TEF-1 (H-4)

View all literature mentions

YAP (63.7) (antibody)

RRID:AB_1131430

This monoclonal targets YAP (63.7)

View all literature mentions

Caveolin-1 (D46G3) XP Rabbit mAb (antibody)

RRID:AB_2275453

This monoclonal targets Caveolin-1

View all literature mentions

14-3-3 η (D23B7) Rabbit mAb (antibody)

RRID:AB_10829034

This monoclonal targets 14-3-3 η

View all literature mentions

LATS1 Antibody (antibody)

RRID:AB_2296754

This polyclonal targets LATS1

View all literature mentions

Goat anti-Mouse IgG (H+L) Secondary Antibody, HRP (antibody)

RRID:AB_228307

This polyclonal secondary targets IgG (H+L)

View all literature mentions

Rho GDIalpha (A-20) (antibody)

RRID:AB_2227516

This polyclonal targets ARHGDIA

View all literature mentions

H3-celegans (antibody)

RRID:AB_302613

This polyclonal targets H3

View all literature mentions

YAP (D8H1X) XP Rabbit mAb (antibody)

RRID:AB_2650491

This recombinant monoclonal targets YAP

View all literature mentions

HeLa (cell line)

RRID:CVCL_0030

Cell line HeLa is a Cancer cell line with a species of origin Homo sapiens

View all literature mentions

MDA-MB-231 (cell line)

RRID:CVCL_0062

Cell line MDA-MB-231 is a Cancer cell line with a species of origin Homo sapiens (Human)

View all literature mentions

YAP (63.7) (antibody)

RRID:AB_1131430

This monoclonal targets YAP (63.7)

View all literature mentions

Caveolin-1 (D46G3) XP Rabbit mAb (antibody)

RRID:AB_2275453

This monoclonal targets Caveolin-1

View all literature mentions

TEF-1 (H-4) (antibody)

RRID:AB_10988229

This monoclonal targets TEF-1 (H-4)

View all literature mentions