Phosphoinositide 3-Kinase C2beta regulates cytoskeletal organization and cell migration via Rac-dependent mechanisms.
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 II 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 C2beta (PI3KC2beta) 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 PI3KC2beta 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 PI3KC2beta reduced Rac activity, membrane ruffling, and cell migration. Moreover, PI3KC2beta-overexpressing cells were protected from anoikis and displayed enhanced proliferation, independently of Rac function. Taken together, these findings suggest that PI3KC2beta regulates the migration and survival of human tumor cells by distinct molecular mechanisms.
Katso
Roy M
RM
Ludwig Institute for Cancer Research, Royal Free and University College Hospital Medical School, London W1W 7BS, United Kingdom.
Pardo
Olivier E
OE
Palamidessi
Andrea
A
Franz
Clemens M
CM
Marinov
Marin
M
De Laurentiis
Angela
A
Downward
Julian
J
Scita
Giorgio
G
Ridley
Anne J
AJ
Waterfield
Michael D
MD
Arcaro
Alexandre
A
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D022005:Adherens Junctions / Q000378:metabolism; D023102:Anoikis / Q000502:physiology; D015820:Cadherins / Q000378:metabolism; D002465:Cell Movement; D049109:Cell Proliferation; D058541:Class II Phosphatidylinositol 3-Kinases; D003598:Cytoskeletal Proteins / Q000378:metabolism; D003599:Cytoskeleton / Q000378:metabolism*; D004847:Epithelial Cells / Q000166:cytology; D051380:GRB2 Adaptor Protein / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D046912:Multiprotein Complexes / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011485:Protein Binding; D020837:SOS1 Protein / Q000378:metabolism; D055765:Shc Signaling Adaptor Proteins; D015398:Signal Transduction; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D014162:Transfection; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*
C513733:ABI1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D015820:Cadherins; D003598:Cytoskeletal Proteins; C489989:EPS8 protein, human; D051380:GRB2 Adaptor Protein; D047908:Intracellular Signaling Peptides and Proteins; D046912:Multiprotein Complexes; C528024:SHC1 protein, human; D020837:SOS1 Protein; D055765:Shc Signaling Adaptor Proteins; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D019869:Phosphatidylinositol 3-Kinases; D058541:Class II Phosphatidylinositol 3-Kinases; C502616:PIK3C2B protein, human; D020830:rac1 GTP-Binding Protein