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CDK5 is a major regulator of the tumor suppressor DLC1

DLC1 is a tumor suppressor protein whose full activity depends on its presence at focal adhesions, its Rho–GTPase activating protein (Rho-GAP) function, and its ability to bind several ligands, including tensin and talin. However, the mechanisms that regulate and coordinate these activities remain p...

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Autores principales: Tripathi, Brajendra K., Qian, Xiaolan, Mertins, Philipp, Wang, Dunrui, Papageorge, Alex G., Carr, Steven A., Lowy, Douglas R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4259810/
https://www.ncbi.nlm.nih.gov/pubmed/25452387
http://dx.doi.org/10.1083/jcb.201405105
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author Tripathi, Brajendra K.
Qian, Xiaolan
Mertins, Philipp
Wang, Dunrui
Papageorge, Alex G.
Carr, Steven A.
Lowy, Douglas R.
author_facet Tripathi, Brajendra K.
Qian, Xiaolan
Mertins, Philipp
Wang, Dunrui
Papageorge, Alex G.
Carr, Steven A.
Lowy, Douglas R.
author_sort Tripathi, Brajendra K.
collection PubMed
description DLC1 is a tumor suppressor protein whose full activity depends on its presence at focal adhesions, its Rho–GTPase activating protein (Rho-GAP) function, and its ability to bind several ligands, including tensin and talin. However, the mechanisms that regulate and coordinate these activities remain poorly understood. Here we identify CDK5, a predominantly cytoplasmic serine/threonine kinase, as an important regulator of DLC1 functions. The CDK5 kinase phosphorylates four serines in DLC1 located N-terminal to the Rho-GAP domain. When not phosphorylated, this N-terminal region functions as an autoinhibitory domain that places DLC1 in a closed, inactive conformation by efficiently binding to the Rho-GAP domain. CDK5 phosphorylation reduces this binding and orchestrates the coordinate activation DLC1, including its localization to focal adhesions, its Rho-GAP activity, and its ability to bind tensin and talin. In cancer, these anti-oncogenic effects of CDK5 can provide selective pressure for the down-regulation of DLC1, which occurs frequently in tumors, and can contribute to the pro-oncogenic activity of CDK5 in lung adenocarcinoma.
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spelling pubmed-42598102015-06-08 CDK5 is a major regulator of the tumor suppressor DLC1 Tripathi, Brajendra K. Qian, Xiaolan Mertins, Philipp Wang, Dunrui Papageorge, Alex G. Carr, Steven A. Lowy, Douglas R. J Cell Biol Research Articles DLC1 is a tumor suppressor protein whose full activity depends on its presence at focal adhesions, its Rho–GTPase activating protein (Rho-GAP) function, and its ability to bind several ligands, including tensin and talin. However, the mechanisms that regulate and coordinate these activities remain poorly understood. Here we identify CDK5, a predominantly cytoplasmic serine/threonine kinase, as an important regulator of DLC1 functions. The CDK5 kinase phosphorylates four serines in DLC1 located N-terminal to the Rho-GAP domain. When not phosphorylated, this N-terminal region functions as an autoinhibitory domain that places DLC1 in a closed, inactive conformation by efficiently binding to the Rho-GAP domain. CDK5 phosphorylation reduces this binding and orchestrates the coordinate activation DLC1, including its localization to focal adhesions, its Rho-GAP activity, and its ability to bind tensin and talin. In cancer, these anti-oncogenic effects of CDK5 can provide selective pressure for the down-regulation of DLC1, which occurs frequently in tumors, and can contribute to the pro-oncogenic activity of CDK5 in lung adenocarcinoma. The Rockefeller University Press 2014-12-08 /pmc/articles/PMC4259810/ /pubmed/25452387 http://dx.doi.org/10.1083/jcb.201405105 Text en This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).
spellingShingle Research Articles
Tripathi, Brajendra K.
Qian, Xiaolan
Mertins, Philipp
Wang, Dunrui
Papageorge, Alex G.
Carr, Steven A.
Lowy, Douglas R.
CDK5 is a major regulator of the tumor suppressor DLC1
title CDK5 is a major regulator of the tumor suppressor DLC1
title_full CDK5 is a major regulator of the tumor suppressor DLC1
title_fullStr CDK5 is a major regulator of the tumor suppressor DLC1
title_full_unstemmed CDK5 is a major regulator of the tumor suppressor DLC1
title_short CDK5 is a major regulator of the tumor suppressor DLC1
title_sort cdk5 is a major regulator of the tumor suppressor dlc1
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4259810/
https://www.ncbi.nlm.nih.gov/pubmed/25452387
http://dx.doi.org/10.1083/jcb.201405105
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