1. PRO, Reactome, And Disease Pathways Peter D’Eustachio NYU School of Medicine

2. Human PIP3- activated AKT signaling

3. Pathway (GO biological process) Pathway Reaction CatalystActivity (GO molecular function) Output 1 Reaction Input 1 Input 2 Output 2 Regulation location (GO cell component) protein (UniProt), DNA/RNA (Ensembl),  molecule (ChEBI) or complex (PRO/GO) Reactome annotation of a normal cellular process

4. Normal (regulated) human PIP3-activated AKT signaling

5. 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.

6. But not all abnormality: successful recognition and neutralization of potentially infectious entities by TLRs

7. Pathway (GO biological process pathogenesis) Pathway Reaction absent or altered CatalystActivity (“not” GO molecular function?) Output 1 Reaction Input 1 Input 2 Output 2 altered regulation location (GO cell component) variant protein (UniProt), DNA/RNA (Ensembl),  molecule (ChEBI) or complex (PRO/GO) Reactome annotation of a disease process

8. Abnormal (constitutive) human PIP3-activated AKT signaling

9. Reaction: PI3K gain of function mutants phosphorylate PIP2 to PIP3

10. Disease

11. Reaction: PI3K gain of function mutants phosphorylate PIP2 to PIP3 Catalyst activity

12. Reaction: PI3K gain of function mutants phosphorylate PIP2 to PIP3 Physical entity

13. Reaction: PI3K gain of function mutants phosphorylate PIP2 to PIP3 Modified residue

14. Reaction: PI3K gain of function mutants phosphorylate PIP2 to PIP3 Entity functional status

15. Reaction: PI3K gain of function mutants phosphorylate PIP2 to PIP3

16. Creighton et al. Nature 499: 43-49 (2013) Increased gene expression in clear cell renal carcinoma correlated with better (blue) or worse (red) survival

17. OICR / CSHL Lincoln Stein Marc Gillespie Robin Haw Bruce May Marija Orlic-Milacic Karen Rothfels Joel Weiser Guanming Wu Credits NHGRI Grant # U41 HG003751 EBI Henning Hermjakob Ewan Birney Antonio Fabregat-Mundo Phani Garapati Bijay Jassal Steve Jupe NYU Peter D'Eustachio Lisa Matthews Veronica Shamovsky EU 6th Framework Programme grant LSHG-CT-2005-518254 "ENFIN"