Activation of phosphatidylinositol 3-kinase in cells expressing abl oncogene variants.
A phosphoinositide kinase specific for the D-3 position of the inositol ring, phosphatidylinositol (PI) 3-kinase, associates with activated receptors for platelet-derived growth factor, insulin, and colony-stimulating factor 1, with products of the oncogenes src, fms, yes, crk, and with polyomavirus middle T antigen. Efficient fibroblast transformation by proteins of the abl and src oncogene families requires activation of their protein-tyrosine kinase activity and membrane association via an amino-terminal myristoylation. We have demonstrated that the PI 3-kinase directly associates with autophosphorylated, activated protein-tyrosine kinase variants of the abl protein. In vivo, this association leads to accumulation of the highly phosphorylated products of PI 3-kinase, PI-3,4-bisphosphate and PI-3,4,5-trisphosphate, only in myristoylated, transforming abl protein variants. Myristoylation thus appears to be required to recruit PI 3-kinase activity to the plasma membrane for in vivo activation and correlates with the mitogenicity of the abl protein variants.
Varticovski
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Department of Biomedical Research, St. Elizabeth's Hospital, Boston, Massachusetts 02135.
Daley
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GQ
Jackson
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Baltimore
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D
Cantley
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LC
D000818:Animals; D002460:Cell Line; D002462:Cell Membrane / Q000201:enzymology; D002471:Cell Transformation, Neoplastic; D004789:Enzyme Activation; D016313:Genes, abl; D014644:Genetic Variation; D051379:Mice; D016374:Oncogene Proteins v-abl / Q000302:isolation & purification; D019869:Phosphatidylinositol 3-Kinases; D010770:Phosphotransferases / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*
D016374:Oncogene Proteins v-abl; D010770:Phosphotransferases; D019869:Phosphatidylinositol 3-Kinases