title: CDK5 is a major regulator of the tumor suppressor DLC1.
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.
authors.affiliation: Laboratory of Cellular Oncology, National Cancer Institute, National Institutes of Health, Bethesda 20892, MD lowyd@mail.nih.gov tripathib@mail.nih.gov.
authors.forename: Brajendra K
authors.initials: BK
authors.lastname: Tripathi
authors.affiliation: Laboratory of Cellular Oncology, National Cancer Institute, National Institutes of Health, Bethesda 20892, MD.
authors.forename: Xiaolan
authors.initials: X
authors.lastname: Qian
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge 02142, MA.
authors.forename: Philipp
authors.initials: P
authors.lastname: Mertins
authors.affiliation: Laboratory of Cellular Oncology, National Cancer Institute, National Institutes of Health, Bethesda 20892, MD.
authors.forename: Dunrui
authors.initials: D
authors.lastname: Wang
authors.affiliation: Laboratory of Cellular Oncology, National Cancer Institute, National Institutes of Health, Bethesda 20892, MD.
authors.forename: Alex G
authors.initials: AG
authors.lastname: Papageorge
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge 02142, MA.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Carr
authors.affiliation: Laboratory of Cellular Oncology, National Cancer Institute, National Institutes of Health, Bethesda 20892, MD lowyd@mail.nih.gov tripathib@mail.nih.gov.
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Lowy
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D045744:Cell Line, Tumor; D051360:Cyclin-Dependent Kinase 5 / Q000502:physiology*; D022001:Focal Adhesions / Q000378:metabolism; D020690:GTPase-Activating Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: C112352:DLC1 protein, human; D020690:GTPase-Activating Proteins; D025521:Tumor Suppressor Proteins; D051360:Cyclin-Dependent Kinase 5; C495905:CDK5 protein, human