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CDK5 is a major regulator of the tumor suppressor DLC1

Item Type:Article
Title:CDK5 is a major regulator of the tumor suppressor DLC1
Creators Name:Tripathi, B.K. and Qian, X. and Mertins, P. and Wang, D. and Papageorge, A.G. and Carr, S.A. and Lowy, D.R.
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.
Keywords:Amino Acid Sequence, Amino Acid Substitution, Cyclin-Dependent Kinase 5, Focal Adhesions, GTPase-Activating Proteins, HEK293 Cells, Molecular Sequence Data, Phosphorylation, Post-Translational Protein Processing, Protein Binding, Protein Interaction Domains and Motifs, Protein Transport, Tumor Cell Line, Tumor Suppressor Proteins, Animals, Mice
Source:Journal of Cell Biology
Publisher:Rockefeller University Press
Page Range:627-642
Date:8 December 2014
Official Publication:https://doi.org/10.1083/jcb.201405105
PubMed:View item in PubMed

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