PAK proteins and YAP-1 signalling downstream of integrin beta-1 in myofibroblasts promote liver fibrosis
| Autor: | Martin, Katherine, Pritchett, James, Llewellyn, Jessica, Mullan, Aoibheann F., Athwal, Varinder S., Dobie, Ross, Harvey, Emma, Zeef, Leo, Farrow, Stuart, Streuli, Charles, Henderson, Neil C., Friedman, Scott L., Hanley, Neil A., Piper Hanley, Karen |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
Liver Cirrhosis
Male Myosin Light Chains Science Integrin beta1 YAP-Signaling Proteins Phosphoproteins Article Mice Inbred C57BL Rats Sprague-Dawley Phenotype p21-Activated Kinases Hepatic Stellate Cells Animals Humans Myofibroblasts Adaptor Proteins Signal Transducing Signal Transduction Transcription Factors |
| Zdroj: | Martin, K, Pritchett, J, Llewellyn, J, Mullan, A F, Athwal, V S, Dobie, R, Harvey, E, Zeef, L, Farrow, S, Streuli, C, Henderson, N C, Friedman, S L, Hanley, N A & Hanley, K P 2016, ' PAK proteins and YAP-1 signalling downstream of integrin beta-1 in myofibroblasts promote liver fibrosis ', Nature Communications, vol. 7, 12502 . https://doi.org/10.1038/ncomms12502 Nature Communications Nature Communications, Vol 7, Iss 1, Pp 1-11 (2016) |
| DOI: | 10.1038/ncomms12502 |
| Popis: | Fibrosis due to extracellular matrix (ECM) secretion from myofibroblasts complicates many chronic liver diseases causing scarring and organ failure. Integrin-dependent interaction with scar ECM promotes pro-fibrotic features. However, the pathological intracellular mechanism in liver myofibroblasts is not completely understood, and further insight could enable therapeutic efforts to reverse fibrosis. Here, we show that integrin beta-1, capable of binding integrin alpha-11, regulates the pro-fibrotic phenotype of myofibroblasts. Integrin beta-1 expression is upregulated in pro-fibrotic myofibroblasts in vivo and is required in vitro for production of fibrotic ECM components, myofibroblast proliferation, migration and contraction. Serine/threonine-protein kinase proteins, also known as P21-activated kinase (PAK), and the mechanosensitive factor, Yes-associated protein 1 (YAP-1) are core mediators of pro-fibrotic integrin beta-1 signalling, with YAP-1 capable of perpetuating integrin beta-1 expression. Pharmacological inhibition of either pathway in vivo attenuates liver fibrosis. PAK protein inhibition, in particular, markedly inactivates the pro-fibrotic myofibroblast phenotype, limits scarring from different hepatic insults and represents a new tractable therapeutic target for treating liver fibrosis. Antifibrotic therapies that target myofibroblast activation are needed to treat chronic liver disease. Here the authors identify an axis of integrin beta-1 expression and Yap-1 and Pak protein signalling that can be interfered with to inhibit myofibroblast function and liver fibrosis in vivo. |
| Databáze: | OpenAIRE |
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