title: PKA-regulated VASP phosphorylation promotes extrusion of transformed cells from the epithelium.
abstract: At the early stages of carcinogenesis, transformation occurs in single cells within tissues. In an epithelial monolayer, such mutated cells are recognized by their normal neighbors and are often apically extruded. The apical extrusion requires cytoskeletal reorganization and changes in cell shape, but the molecular switches involved in the regulation of these processes are poorly understood. Here, using stable isotope labeling by amino acids in cell culture (SILAC)-based quantitative mass spectrometry, we have identified proteins that are modulated in transformed cells upon their interaction with normal cells. Phosphorylation of VASP at serine 239 is specifically upregulated in Ras(V12)-transformed cells when they are surrounded by normal cells. VASP phosphorylation is required for the cell shape changes and apical extrusion of Ras-transformed cells. Furthermore, PKA is activated in Ras-transformed cells that are surrounded by normal cells, leading to VASP phosphorylation. These results indicate that the PKA-VASP pathway is a crucial regulator of tumor cell extrusion from the epithelium, and they shed light on the events occurring at the early stage of carcinogenesis.
authors: Department of Cell Biology, UCL Institute of Ophthalmology, University College London, London EC1V 9EL, UK MRC Laboratory for Molecular Cell Biology and Cell Biology Unit, University College London, London WC1E 6BT, UK.
authors: Katarzyna A
authors: KA
authors: Anton
authors: Division of Cancer Biology, Cell Communication Team, The Institute of Cancer Research, London SW3 6JB, UK.
authors: John
authors: J
authors: Sinclair
authors: Division of Molecular Oncology, Institute for Genetic Medicine, Hokkaido University, Sapporo 060-0815, Japan.
authors: Atsuko
authors: A
authors: Ohoka
authors: Division of Molecular Oncology, Institute for Genetic Medicine, Hokkaido University, Sapporo 060-0815, Japan.
authors: Mihoko
authors: M
authors: Kajita
authors: Division of Molecular Oncology, Institute for Genetic Medicine, Hokkaido University, Sapporo 060-0815, Japan.
authors: Susumu
authors: S
authors: Ishikawa
authors: Institute for Vascular Signaling, University of Frankfurt, Frankfurt D-60590, Germany.
authors: Peter M
authors: PM
authors: Benz
authors: Department of Molecular Medicine and Surgery and Center for Molecular Medicine, Karolinska Institute, Stockholm SE-171 77, Sweden Institute for Clinical Chemistry, University Hospital Hamburg-Eppendorf, Hamburg 20246, Germany.
authors: Thomas
authors: T
authors: Renne
authors: Department of Cell Biology, UCL Institute of Ophthalmology, University College London, London EC1V 9EL, UK.
authors: Maria
authors: M
authors: Balda
authors: Division of Cancer Biology, Cell Communication Team, The Institute of Cancer Research, London SW3 6JB, UK k.matter@ucl.ac.uk yasu@igm.hokudai.ac.jp.
authors: Claus
authors: C
authors: Jorgensen
authors: Department of Cell Biology, UCL Institute of Ophthalmology, University College London, London EC1V 9EL, UK k.matter@ucl.ac.uk yasu@igm.hokudai.ac.jp.
authors: Karl
authors: K
authors: Matter
authors: MRC Laboratory for Molecular Cell Biology and Cell Biology Unit, University College London, London WC1E 6BT, UK Division of Molecular Oncology, Institute for Genetic Medicine, Hokkaido University, Sapporo 060-0815, Japan k.matter@ucl.ac.uk yasu@igm.hokudai.ac.jp.
authors: Yasuyuki
authors: Y
authors: Fujita
mesh_terms: D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D002461:Cell Line, Transformed; D002471:Cell Transformation, Neoplastic; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism*; D004847:Epithelial Cells / Q000201:enzymology / Q000378:metabolism; D004848:Epithelium / Q000201:enzymology / Q000378:metabolism*; D006801:Humans; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism; D000098662:Vasodilator-Stimulated Phosphoprotein
chemical_list: D015815:Cell Adhesion Molecules; D008840:Microfilament Proteins; D010750:Phosphoproteins; D000098662:Vasodilator-Stimulated Phosphoprotein; D017868:Cyclic AMP-Dependent Protein Kinases; D016283:Proto-Oncogene Proteins p21(ras)
keywords: Apical extrusion; PKA; Ras-transformed; VASP