title: The tumor suppressor protein DLC1 is regulated by PKD-mediated GAP domain phosphorylation.
abstract: Deleted in liver cancer 1 (DLC1) is a tumor suppressor protein that is frequently downregulated in various tumor types. DLC1 contains a Rho GTPase activating protein (GAP) domain that appears to be required for its tumor suppressive functions. Little is known about the molecular mechanisms that regulate DLC1. By mass spectrometry we have mapped a novel phosphorylation site within the DLC1 GAP domain on serine 807. Using a phospho-S807-specific antibody, our results identify protein kinase D (PKD) to phosphorylate this site in DLC1 in intact cells. Although phosphorylation on serine 807 did not directly impact on in vitro GAP activity, a DLC1 serine-to-alanine exchange mutant inhibited colony formation more potently than the wild type protein. Our results thus show that PKD-mediated phosphorylation of DLC1 on serine 807 negatively regulates DLC1 cellular function.
authors.affiliation: University of Stuttgart, Institute of Cell Biology and Immunology, Allmandring 31, 70569 Stuttgart, Germany.
authors.forename: Rolf-Peter
authors.initials: RP
authors.lastname: Scholz
authors.forename: Johan O R
authors.initials: JO
authors.lastname: Gustafsson
authors.forename: Peter
authors.initials: P
authors.lastname: Hoffmann
authors.forename: Mamta
authors.initials: M
authors.lastname: Jaiswal
authors.forename: Mohammed Reza
authors.initials: MR
authors.lastname: Ahmadian
authors.forename: Stephan A
authors.initials: SA
authors.lastname: Eisler
authors.forename: Patrik
authors.initials: P
authors.lastname: Erlmann
authors.forename: Simone
authors.initials: S
authors.lastname: Schmid
authors.forename: Angelika
authors.initials: A
authors.lastname: Hausser
authors.forename: Monilola A
authors.initials: MA
authors.lastname: Olayioye
mesh_terms: D001665:Binding Sites; D045744:Cell Line, Tumor; D015536:Down-Regulation; D005260:Female; D020690:GTPase-Activating Proteins / Q000378:metabolism* / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D013058:Mass Spectrometry; D010766:Phosphorylation; D054730:Protein Interaction Domains and Motifs / Q000502:physiology*; D011493:Protein Kinase C / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: C112352:DLC1 protein, human; D020690:GTPase-Activating Proteins; D025521:Tumor Suppressor Proteins; C085379:rho GTPase-activating protein; C089212:protein kinase D; D011493:Protein Kinase C