Rare cancer-specific mutations in PIK3CA show gain of function

摘要: Fifteen rare cancer-derived mutants of PIK3CA, the gene coding for catalytic subunit p110α phosphatidylinositol 3-kinase (PI3K), were examined their biological and biochemical properties. Fourteen these show a gain function: they induce rapamycin-sensitive oncogenic transformation chicken embryo fibroblasts, constitutively activate Akt TOR-mediated signaling, enhanced lipid kinase activity. Mapping on partial structural model suggests three groups mutants, defined by location in distinct functional domains protein. We hypothesize that each induces PI3K function different molecular mechanism. Mutants C2 domain increase positive surface charge this therefore may enhance recruitment to cellular membranes. helical map contiguous protein affect interaction with other protein(s). are located near hinge activation loop. They alter position mobility Arbitrarily introduced mutations have no detectable phenotype either interior or positioned region lies opposite exposed surfaces containing gain-of-function mutants. Engineered exchange acidic neutral residues basic critical function.