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

TY - JOUR

T1 - PKA-regulated VASP phosphorylation promotes extrusion of transformed cells from the epithelium

AU - Anton, Katarzyna A

AU - Sinclair, John

AU - Ohoka, Atsuko

AU - Kajita, Mihoko

AU - Ishikawa, Susumu

AU - Benz, Peter M

AU - Renne, Thomas

AU - Balda, Maria

AU - Jorgensen, Claus

AU - Matter, Karl

AU - Fujita, Yasuyuki

N1 - © 2014. Published by The Company of Biologists Ltd.

PY - 2014/8/15

Y1 - 2014/8/15

N2 - 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.

AB - 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.

U2 - 10.1242/jcs.149674

DO - 10.1242/jcs.149674

M3 - SCORING: Journal article

C2 - 24963131

VL - 127

SP - 3425

EP - 3433

JO - J CELL SCI

JF - J CELL SCI

SN - 0021-9533

IS - 16

ER -