Activation and nuclear translocation of mitogen-activated protein kinases by polyomavirus middle-T or serum depend on phosphatidylinositol 3-kinase.
Several cellular signal transduction pathways activated by middle-T in polyomavirus-transformed cells are required for viral oncogenicity. Here we focus on the role of phosphatidylinositol 3-kinase (PI 3-kinase) and Ras and address the question how these signaling molecules cooperate during cell cycle activation. Ras activation is mediated through association with SHC.GRB2.SOS and leads to increased activity of several members of the mitogen-activated protein (MAP) kinase family, while activation of PI 3-kinase results in the generation of D3-phosphorylated phosphatidylinositides whose downstream targets remain elusive. PI 3-kinase activation might also ensue as a direct consequence of Ras activation. Oncogenicity of middle-T requires stimulation of both Ras- and PI 3-kinase-dependent pathways. Mutants of middle-T incapable to bind either SHC.GRB2.SOS or PI 3-kinase are not oncogenic. Sustained activation and nuclear localization of one of the MAP kinases, ERK1, was observed in wild type but not in mutant middle-T-expressing cells. Wortmannin, an inhibitor of PI 3-kinase, prevented MAP kinase activation and nuclear localization in middle-T-transformed cells. PI 3-kinase activity was also required for activation of the MAP kinase pathway in normal serum-stimulated cells, generalizing the concept that signaling through MAP kinases requires not only Ras-but also PI 3-kinase-mediated signals.
D016475:3T3 Cells; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000502:physiology*; D001692:Biological Transport; D001790:Blood Physiological Phenomena; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002467:Cell Nucleus / Q000201:enzymology; D002471:Cell Transformation, Neoplastic; D004789:Enzyme Activation; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000502:physiology*; D011120:Polyomavirus / Q000276:immunology*; D011401:Promoter Regions, Genetic; D051381:Rats; D011916:Rats, Inbred F344; D000077191:Wortmannin
D000730:Androstadienes; D000952:Antigens, Polyomavirus Transforming; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); D017871:Calcium-Calmodulin-Dependent Protein Kinases; D000077191:Wortmannin