CDK5 is a major regulator of the tumor suppressor DLC1 |
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| Authors: | Brajendra K Tripathi Xiaolan Qian Philipp Mertins Dunrui Wang Alex G Papageorge Steven A Carr Douglas R Lowy |
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| Institution: | 1Laboratory of Cellular Oncology, National Cancer Institute, National Institutes of Health, Bethesda 20892, MD;2The Broad Institute of MIT and Harvard, Cambridge 02142, MA |
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| Abstract: | 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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