A Knowledge Model for Analysis and Simulation of

Signal Transduction Networks

Our project is set up as a collaboration of three departments of Columbia University

Columbia Genome Center

Computer Science

Department of Medical Informatics

Authors:

Tomohiro Koike, Sergey Kalachikov, Shawn M. Gomez,

Michael Krauthammer, Sabina H. Kaplan,

Pauline Kra, James J. Russo, Carol Friedman,Andrey Rzhetsky

Ontology:

•collection of concepts

•concept definitions •relationships among concepts•properties of each concept •[explicit axioms]

Goal – a Particular Application

Problem/Motivation:

Currently a search through the PubMed system with the keywords “cell cycle” and “apoptosis” produced lists of 169,293 and 29,961 articles, respectively.

Clearly it is not feasible to scan all these papers “manually” ...

Outline of the

system that we

are designing

Relevantkeywords

Pathways

V isula ize

Edit

S im ulate

Com pare

Retrieve collection ofjournal artic les

Save collection ofstatem ent/source

pairs

Natuaral Language Processing

F ilterstatem ents,

resolvecontroversies,

e lim inateredundancies

In s ilicoknock out

or knock ingenes

Basic concepts

Action, ActionAgent, Process, Publication, Taxon, Disease, Mechanism, Result, Developmental Stage, MicroStructure, State, MacroStructure, Relation, Similarity, RelationType, and ActionTemplate

We represent a pathway a series of overlapping “links” –

substance/action/substance triplets

Substance A Substance B Substance C Substance D

Representation

ActionAgent

6. PublicationBook

Article

URL

Database

3. Effect

2. ActionAgent

4. Substance

Protein DNA

RNA

Sm all Molecule

Com plex

Lipid

Carbohydrate

Nucleic Acid

Lipoprotein

Glycoprotein

Glycolipid

Nucleotide

Am ino acid

Gene

Oligonucleotide

Heat shock Cold shock

Osm otic shock Radiation

Action and Process

1. Action5. ProcessTranslation

Transcription

Apoptosis

Grow th

MovementCell-Cell interaction

Cell-Matrix interaction

Uptake

Killing

Auxiliary Concepts

Publication, Taxon, Structure, Developmental Stage, and Disease encapsulate pieces of auxiliary information about ActionAgents, Processes and Actions

Properties of Concepts: ActionAgent

4. Substance:N am e(s)

Publication(s)

3. Effect:N am e(s)

2. ActionAgent:C onceptID

Properties of Concepts: Action

1. Action:N am e(s)

C onceptIDU pstream ActionAgent(s)

D ownstream ActionAgent(s)C ata lystActionAgent(s)

S ideActionAgent(s)K ineticC onstant(s)

Publication(s)R esult(s)

M echanism

Duality of actions in signal transduction literature

Dualism: in the biochemical representation substance A is not a participant of the

action, while it is in the logical representation

Logical Biochemical

Logic RepresentationBiochemical

Representation Example

A = P I 3KB = A K T /P K B

A = pro te inphospatase 2A

B = FA S -activa ted

serine /th reon inekinase

A = IC EB = C P P 32

A = FA S -LB = FA S

A = (C -M yc:M ax)pro te in com plex

B = cdc25A gene

A = e IF2BB = virtua lly any

gene

A = C a pum pA T P aseB = C a

2+

2+

A

B

A T P

A D P +

(pum p/channe l)

ins ide

B outs ide

-P O4

A

B

(ca ta lyst - phosphatase )

active

B inactive

phosphoryla ted

-P O4

A

B

A T P

A D P

(ca ta lyst - kinase )

active

B inactive

phosphoryla ted

Bactive

C inactive

D +

A (ca ta lyst - pro tease )

A is a ligand

B inactiveA +

active[AB ]B is a receptor

A in itia tes transcrip tion o f B

phosphoryla tion

dephosphoryla tion

transport

c leavage

b ind ing

transcrip tion

transla tion A in itia tes transla tion of B

A activa tes B th rough a processprocess A = FA S -LB = A K T /P K B

A activa tes B th rough an action

other

single action

A

B

"A activates B"

We realized that the

current research literature in molecular biology

Describes pathways on two different levels:

Logical

and

Biochemical

A activates BA inactivates B

A phoshorylates BA methylates B

...

logical

biochemical

Both logical and biochemical descriptions can be combined in the same sentence:

Activated raf-1 phosphorylates and activates mek-1.

logicalbiochemical

Mechanism and Result of an Action

10. Result:C onceptID

Activate:

Inactivate:

8. Disease:N am e(s)

C onceptID

9. M echanism :C onceptID

Bind:S ites

Release:S ites

Modify:S ites

Transport:

CreateBond:N am e

BreakBond:N am e

"Phosphorylate"

"Dephosphorylate"

"Cleave"

"Dem ethylate"

"Rem oveN-Signal"

"BreakCys-CysBond"

"Acetylate"

"Ubiquitinize" "M ethylate"

"M akeCys-CysBond"

"Acylate" "Glycosylate"

"Hydroxylate"

e .g .,

e .g .,

"NucleotideExchange"

Mechanism and Result

Result LogicalAction

Mechanism BiochemicalAction

Converting LogicalAction into BiochemicalAction and back

18. ActionT em plate:Nam e

LogicalActionBiochem icalAction

Example:

ActionT emplate:Nam e Phosporylation

LogicalAction:Nam e(s)

Upstream ActionAgent(s)Downstewam ActionAgent(s)

CatalystActionAgent(s)S ideActionAgent(s)K ineticConstant(s)

Publication(s)Result(s)

M echanism

?AB???PublicationActivationPhosphorylate

?ATP, dephosphorylated B, AADP, phosphorylated B , AAATP, ADP?PublicationActivationPhosphorylate

Biochem icalAction:Nam e(s)

Upstream ActionAgent(s)Downstewam ActionAgent(s)

CatalystActionAgent(s)S ideActionAgent(s)K ineticConstant(s)

Publication(s)Result(s)

M echanism

"A phosphorylates and activates B "

1. Action:

The paper descibing this ontology will appear in Bioinformatics

A. Rzhetsky, T. Koike, S. Kalachikov, S. M. Gomez, M. Krauthammer, S. H. Kaplan, P. Kra, J. J. Russo and C. Friedman, A knowledge model for analysis and simulation of regulatory networks, Bioinformatics, (accepted) (2000).

Implementation: A Pathway Editor

Koike, T., and Rzhetsky, A. 2000. A graphic editor for analyzing signal transduction pathways. Gene (accepted).

Human cell cycle/apoptosis pathways

Small fragment of the same pathway

IL -3

IL -3R

IG F1

IG F1R

IR S 1

R A S

P I 3-K

A K T/P K B

B A D

B cl-XL

FA S -L

FA S

FA DD/MO R T

FL IC E

IC E

C P P 32

apoptos is

m itogen

C yclin D1

pR b

E 2F

C yclin E

P 53

P 21

P 16

P 27

C dk4

P 107

C -Myc

C -Myc

?

B in-1

Max

Max

C dc25A

Max

Mad

Mad

C dk2p

P 27 C yclin E

C dk2p

C yclin E

C dk2 p

C yclin E

C dk2

c ell pro liferation

O snail,climb Mount Fuji

with no hurry

Issa

Thank you!