Phosphoinositide 3-kinase C2 beta regulates cytoskeletal organization and cell migration via Rac-dependent mechanism

TY - JOUR

T1 - Phosphoinositide 3-kinase C2 beta regulates cytoskeletal organization and cell migration via Rac-dependent mechanism

AU - Katso, R M

AU - Pardo, O E

AU - Palamidessi, A

AU - Franz, C M

AU - Marinov, M

AU - De Laurentiis, A

AU - Downward, J

AU - Scita, G

AU - Ridley, A J

AU - Waterfleld, M D

AU - Arcaro, A

PY - 2006/9

Y1 - 2006/9

N2 - Receptor-linked class I phosphoinositide 3-kinases (PI3Ks) induce assembly of signal transduction complexes through protein-protein and protein-lipid interactions that mediate cell proliferation, survival, and migration. Although class 11 PI3Ks have the potential to make the same phosphoinositides as class I PI3Ks, their precise cellular role is currently unclear. In this report, we demonstrate that class II phosphoinositide 3-kinase C2 beta (PI3KC2 beta) associates with the Eps8/Abi1/Sos1 complex and is recruited to the EGF receptor as part of a multiprotein signaling complex also involving Shc and Grb2. Increased expression of PI3KC2 beta stimulated Rac activity in A-431 epidermoid carcinoma cells, resulting in enhanced membrane ruffling and migration speed of the cells. Conversely, expression of dominant negative PI3KC2 beta reduced Rac activity, membrane ruffling, and cell migration. Moreover, PI3KC2 beta-overexpressing cells were protected from anoikis and displayed enhanced proliferation, independently of Rac function. Taken together, these findings suggest that PI3KC2 beta regulates the migration and survival of human tumor cells by distinct molecular mechanisms

AB - Receptor-linked class I phosphoinositide 3-kinases (PI3Ks) induce assembly of signal transduction complexes through protein-protein and protein-lipid interactions that mediate cell proliferation, survival, and migration. Although class 11 PI3Ks have the potential to make the same phosphoinositides as class I PI3Ks, their precise cellular role is currently unclear. In this report, we demonstrate that class II phosphoinositide 3-kinase C2 beta (PI3KC2 beta) associates with the Eps8/Abi1/Sos1 complex and is recruited to the EGF receptor as part of a multiprotein signaling complex also involving Shc and Grb2. Increased expression of PI3KC2 beta stimulated Rac activity in A-431 epidermoid carcinoma cells, resulting in enhanced membrane ruffling and migration speed of the cells. Conversely, expression of dominant negative PI3KC2 beta reduced Rac activity, membrane ruffling, and cell migration. Moreover, PI3KC2 beta-overexpressing cells were protected from anoikis and displayed enhanced proliferation, independently of Rac function. Taken together, these findings suggest that PI3KC2 beta regulates the migration and survival of human tumor cells by distinct molecular mechanisms

U2 - 10.1091/mbc.E05-11-1083

DO - 10.1091/mbc.E05-11-1083

M3 - Article

VL - 17

SP - 3729

EP - 3744

JO - Molecular Biology of the Cell

JF - Molecular Biology of the Cell

IS - 9

ER -