Extended Data Fig. 11: Molecular mechanism underlying the enhanced functional activity of oncogenic MMs.
From: Landscape and function of multiple mutations within individual oncogenes
a, Fraction of PIK3CA copy-number (CN) alterations according to PIK3CA MM status for 385 UCEC patients in TCGA. b, Fraction of PIK3R1 and PTEN mutations according to PIK3CA MM status for 1,339 UCEC patients in the total cohort. a, b, Two-sided Fisher’s exact test. Single mutations were classified into missense mutations in major and minor hotspot positions, in-frame indels, and non-hotspot/functional mutations, some of which are not shown owing to small numbers. Examined numbers are shown in parentheses. c, The distance between key residues of the p110α/p85α complex16. Data represent means + s.d. (250–500 ns). d, Distance between R88 and D746 atoms. e, Distance between R38 and D743 atoms. d, e, Data represent means ± s.d. (250–500 ns). c–e, Two-sided Welch’s t-test. d, e, Different colours show independent simulations. f, Overall structure of wild-type PIK3CA (left) and a close-up view of the mean structure at the ABD–kinase interface (right). g, Mean backbone structures of R88Q, H1047R and R88Q–H1047R mutants, showing the orientation of the ABD, kinase and iSH2 (p85α) domains, superimposed on those of the wild type. Movements of the ABD and iSH2 domains induced by each mutant are indicated by arrows, along with the backbone root mean square deviation (r.m.s.d.) of the ABD (residues 16–105; magenta) and iSH2 (490–540; green) domains from the wild-type structure. c–g, Molecular-dynamics simulations for wild-type and each mutant PIK3CA (combined results from three independent 500-ns simulations are shown). h, Dependency of 60 CCLE cell lines from haematopoietic and lymphoid tissue on NOTCH1, with cell lines coloured by MM status, in the DepMap CRISPR–Cas9 knockout data. i, Luciferase assays of TP-1 reporter activity in 293T cells transfected with mock control or the indicated amounts of wild-type, single-mutant or double-mutant NOTCH1 vectors (n = 5). Data represent means + s.d. Two-sided paired t-test on log-transformed values.
