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PRO, Reactome, And Disease Pathways Peter D’Eustachio NYU School of Medicine Human PIP3activated AKT signaling Reactome annotation of a normal cellular process protein (UniProt), DNA/RNA (Ensembl), mmolecule (ChEBI) or complex (PRO/GO) Input 1 Regulation Output 1 Reaction Input 2 location (GO cell component) CatalystActivity (GO molecular function) Pathway (GO biological process) Pathway Reaction Reaction Output 2 Normal (regulated) human PIP3-activated AKT signaling Molecular abnormality leads to disease 1. The mode of expression of a protein is altered. 2.A mutation leads to expression of an inactive protein. 3.A mutation or infection leads to expression of a protein with a novel function. But not all abnormality: successful recognition and neutralization of potentially infectious entities by TLRs Reactome annotation of a disease process altered regulation variant protein (UniProt), DNA/RNA (Ensembl), mmolecule (ChEBI) or complex (PRO/GO) Input 1 Output 1 Reaction Input 2 location (GO cell component) absent or altered CatalystActivity (“not” GO molecular function?) Pathway (GO biological process pathogenesis) Pathway Reaction Reaction Output 2 Abnormal (constitutive) human PIP3-activated AKT signaling Reaction: PI3K gain of function mutants phosphorylate PIP2 to PIP3 Reaction: PI3K gain of function mutants phosphorylate PIP2 to PIP3 Disease Reaction: PI3K gain of function mutants phosphorylate PIP2 to PIP3 Catalyst activity Reaction: PI3K gain of function mutants phosphorylate PIP2 to PIP3 Physical entity Reaction: PI3K gain of function mutants phosphorylate PIP2 to PIP3 Modified residue Reaction: PI3K gain of function mutants phosphorylate PIP2 to PIP3 Entity functional status Reaction: PI3K gain of function mutants phosphorylate PIP2 to PIP3 Increased gene expression in clear cell renal carcinoma correlated with better (blue) or worse (red) survival Creighton et al. Nature 499: 43-49 (2013) Credits OICR / CSHL Lincoln Stein Marc Gillespie Robin Haw Bruce May Marija Orlic-Milacic Karen Rothfels Joel Weiser Guanming Wu EBI Henning Hermjakob Ewan Birney Antonio Fabregat-Mundo Phani Garapati Bijay Jassal Steve Jupe NHGRI Grant # U41 HG003751 NYU Peter D'Eustachio Lisa Matthews Veronica Shamovsky EU 6th Framework Programme grant LSHG-CT-2005-518254 "ENFIN"
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