biostudies-literatureMandelker DNIDDK NIH HHSHoward Hughes Medical InstituteNCI NIH HHSNIGMS NIH HHS16996-7001https://www.ebi.ac.uk/biostudies/studies/S-EPMC2761334biostudies-literatureUnknown106(40)Mutations in oncogenes often promote tumorigenesis by changing the conformation of the encoded proteins, thereby altering enzymatic activity. The PIK3CA oncogene, which encodes p110alpha, the catalytic subunit of phosphatidylinositol 3-kinase alpha (PI3Kalpha), is one of the two most frequently mutated oncogenes in human cancers. We report the structure of the most common mutant of p110alpha in complex with two interacting domains of its regulatory partner (p85alpha), both free and bound to an inhibitor (wortmannin). The N-terminal SH2 (nSH2) domain of p85alpha is shown to form a scaffold for the entire enzyme complex, strategically positioned to communicate extrinsic signals from phosphopeptides to three distinct regions of p110alpha. Moreover, we found that Arg-1047 points toward the celProceedings of the National Academy of Sciences of the United States of AmericaA frequent kinase domain mutation that changes the interaction between PI3Kalpha and the membrane.PMC2761334T32 GM007184CA43460T32 GM007309GM07309P30 DK079637R37 CA043460GM07184Gabelli SBCheong IKinzler KWMandelker DZhu JVogelstein BSchmidt-Kittler OHuang CHAmzel LMfalseA frequent kinase domain mutation that changes the interaction between PI3Kalpha and the membrane.Mutations in oncogenes often promote tumorigenesis by changing the conformation of the encoded proteins, thereby altering enzymatic activity. The PIK3CA oncogene, which encodes p110alpha, the catalytic subunit of phosphatidylinositol 3-kinase alpha (PI3Kalpha), is one of the two most frequently mutated oncogenes in human cancers. We report the structure of the most common mutant of p110alpha in complex with two interacting domains of its regulatory partner (p85alpha), both free and bound to an inhibitor (wortmannin). The N-terminal SH2 (nSH2) domain of p85alpha is shown to form a scaffold for the entire enzyme complex, strategically positioned to communicate extrinsic signals from phosphopeptides to three distinct regions of p110alpha. Moreover, we found that Arg-1047 points toward the cel2009-01-01T00:00:00Z2009 Oct2026-05-05T04:46:25.801Z2019-03-27T00:25:51ZS-EPMC27613341980510510.1073/pnas.0908444106