Journal
JOURNAL OF CELL SCIENCE
Volume 127, Issue 16, Pages 3425-3433Publisher
COMPANY OF BIOLOGISTS LTD
DOI: 10.1242/jcs.149674
Keywords
Apical extrusion; Ras-transformed; VASP; PKA
Categories
Funding
- Medial Research Council
- Vetenskapsradet [21462]
- German Research Society [SFB 841]
- European Research Council [ERC-StG-2012-311575_F-12]
- Cancer Research UK Career Establishment Award [A12905]
- Wellcome Trust [084678/Z/08/Z, 099173/Z/12/Z]
- Biotechnology and Biological Sciences Research Council
- Next Generation World-Leading Researchers (NEXT Program)
- Takeda Science Foundation
- Uehara Memorial Foundation
- Daiichi-Sankyo Foundation of Life Science
- Naito Foundation
- Wellcome Trust [084678/Z/08/Z] Funding Source: Wellcome Trust
- Grants-in-Aid for Scientific Research [26250026] Funding Source: KAKEN
- BBSRC [BB/J015032/1, BB/L007584/1] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/J015032/1, BB/L007584/1] Funding Source: researchfish
- Cancer Research UK [12905] Funding Source: researchfish
- Medical Research Council [MC_CF12266] Funding Source: researchfish
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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 RasV12-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.
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