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J Cell Sci. 2014 Aug 15;127(Pt 16):3425-33. doi: 10.1242/jcs.149674. Epub 2014 Jun 24.

PKA-regulated VASP phosphorylation promotes extrusion of transformed cells from the epithelium.

Author information

1
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.
2
Division of Cancer Biology, Cell Communication Team, The Institute of Cancer Research, London SW3 6JB, UK.
3
Division of Molecular Oncology, Institute for Genetic Medicine, Hokkaido University, Sapporo 060-0815, Japan.
4
Institute for Vascular Signaling, University of Frankfurt, Frankfurt D-60590, Germany.
5
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.
6
Department of Cell Biology, UCL Institute of Ophthalmology, University College London, London EC1V 9EL, UK.
7
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.
8
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.
9
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.

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.

KEYWORDS:

Apical extrusion; PKA; Ras-transformed; VASP

PMID:
24963131
PMCID:
PMC4132389
DOI:
10.1242/jcs.149674
[Indexed for MEDLINE]
Free PMC Article

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