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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...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The Rockefeller University Press
2014
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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. |
format | Online Article Text |
id | pubmed-4259810 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | The Rockefeller University Press |
record_format | MEDLINE/PubMed |
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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