Representation of and Reasoning with signal networks

1. Representation of and Reasoning with signal networks Chitta Baral Arizona State University

2. Existing terminologies • Actions: when they occur they often change the world. • Eg. load, shoot, ligand coming in contact with a receptor • Fluents: property of the world. Eg. Loaded, alive, active • Situations: refers to time moments. s, s1, s2, [a1, a2, …, an], res(a,s) • Initial situation: refers to the initial moment. s0 , [ ] • Current situation: refers to the current moment sc, snow, • States: a view of the world at a particular moment • eg. {~loaded, alive, has_bullet, ~dead} • Plans: simplest ones are a sequence of actions • (Domain) Descriptions: Describe the effect of actions on the world; describe which actions are executable when; describe relations between the objects in the world. • Load causes loaded • Shoot causes ~alive if loaded • Executable load if has_bullet • Always alive  ~dead • Observations: f at s a occurs_at s f after a1, …, anat s • Hypothetical Queries: f after a1, …, an f after a1, …, anat s • Entailment: the relation |= in D,O |= Q. • Can we infer or conclude that Q is true from our knowledge D and observation O.

3. The Yale shooting example • Domain description: D • Load causes loaded • Shoot causes ~alive if loaded • Executable load if has_bullet • Observations: O • Initially alive, has_bullet, ~ loaded • Prediction: • (D, O) |= ~alive after shoot? • S0 = {alive, has_bullet, ~loaded} shoot {alive, has_bullet, ~loaded} • (D,O) |= ~alive after load, shoot? • {alive, has_bullet, ~loaded} load {alive, has_bullet, loaded} shoot {~alive, has_bullet, loaded} • Planning: Find a sequence of actions X such that (D,O) |= ~alive after X. • Actions define transition between states. • Simple planning is to find a path between the initial state (or current state) and one of the desired goal states. • Explanation: Given D, O1 and Q, Find O2 such that (D, O1 U O2) |= Q. • Eg. Find O2 such that (D, {initially alive} U O2) |= ~alive after shoot. • O2 = {initially loaded}

4. Representing the G-protein related pathway • Executable bind(ligand,receptor1) if holds(abg-comp), boundto(abg-comp,gdp), linked_to(abg-comp, receptor1). • bind(ligand,receptor1) causes not_holds(abg-comp), holds(a-comp), boundto(a-comp,gtp), holds(bg-comp),released(gdp). • Executable hydrolysis if holds(a-comp), boundto(a-comp,gtp). • hydrolysis causes boundto(a-comp, gdp). • Executable recombination if holds(a-comp), holds(bg-comp), inactive(a-comp). • Recombination causes holds(abg-comp), not_holds(a-comp), not_holds(bg-comp), boundto(abg-comp,gdp).

5. Bio-chemical terminologies that can be accommodated within existing notions • Bind • Release • Modify: eg. Phosphorylate, dephosphorylate • Activate,Inhibit.

6. New concepts and terminologies – representational challenges • Triggering • Increase and decrease in concentration • Sensitization • Protein `recruiting’ other proteins • DAP3 protein functions as an adaptor or a scaffold to recruit an assembly of proteins to cell receptors known as the Death Receptor 4/5 (DR4/5). • Activated may have different physical meanings • A protein that is `regulatively’ activated can be `physically’ either phosphorylated or dephosphorylated by that activation. • A part of a pathway can be decomposed further at an arbitrary level of detail • Descriptions of signal pathways often do not provide comprehensive information about every relation in the pathway. • An author may omit a well-known portion of the pathway (assuming that the reader is already familiar with it) • A portion of the pathway not clearly understood may also be omitted.

7. Graphical representation(from http://www.afcs.org/cm2/)

9. Glossary of interactions • Transport • the movement of a material from one place to another, eg. The movement of substances around the body in blood, or across a biological membrane, or of electrons a long a series of carriers. • (TRANSLOCATION: the process by which a newly synthesized protein is directed toward a specific cellular compartment. i.e, the nucleus, the endoplasmic reticulum.) • Positive control (activation) • occurs when a specific gene requires the binding of a specific protein (activating protein) in order to achieve RNA polymerase binding and gene expression. The activation protein results in a positive action - gene expression. Any molecule which promotes a certain reaction between other molecules is said to exert positive control over the result of the reaction. • Negative control (inhibition) • occurs when the binding of a specific protein (repressor protein) to DNA at a point that results in interference with the action of RNA polymerase on a specific gene. The repressor protein results in a negative action - lack of gene expression. In addition to negative control of gene expression, any molecule which prevents a certain chemical reaction (e.g. complex formation), is said to exert negative control over the resulting reaction (inhibits complex formation).

10. Glossary of interactions (cont.) • Chemical transformation – see next slides • Induction (of expression) • the process by which a small molecule triggers (induces) the synthesis of a protein or group of proteins by permitting transcription to occur. • Repression (of expression) • the process by which a small molecule inhibits the synthesis of a protein or group of proteins by preventing transcription from occurring.

11. X2 Reversible Reaction X1 X2 Single splitting reaction generating two products X2 and X3, in stoichiometric proportion. X1 X3 X2 Divergence Branch Point: Degradation processes of X1 into X2 and X3 are independent X1 X3 X1 Single synthetic reaction involving two source components X1 and X2, in stoichiometric proportion. X3 X1 Convergence Branch Point: Degradation processes of X1 into X2 and X3 are independent X2 X3 X2 Chemical transformations (ref. Misra)

12. X3 X4 X2 X1 X3 The conversion of X1 into X2 is modulated by X3 X2 X1 X3 The conversion of X1 into X2 is modulated by an inhibitor X3 - X2 X1 Chemical transformations (cont.) – ref. Misra The reaction between X1 and X2 requires coenzyme X3 which is converted to X4

13. An example of chemical transformations: Glycolysis (ref. Misra) Glycogen P_i Glucose Glucose-1-P Phosphorylase a Phosphoglucomutase Glucokinase Glucose-6-P Phosphoglucose isomerase Fructose-6-P Phosphofructokinase

15. Glossary of molecule designations • Receptors (eg. GPCR, RTKs, Cytokine, Nuclear) • GTPases (Ga, Rho, Ras, rab) • (Guanosine triphosphatase) • Enzyme that catalyzes the reaction GTP +H20  Guanosine + Triphosphate • Enzymes (A Cyclase, G cyclase, Lipases, Protease) • Bioactive protein that catalyzes the biochemical reactions in the living cell. • Kinases (S/T, Y, Lipid, Dual) • The enzyme that catalyzes the transfer of a phosphate group from one compound to another. • Phosphatases (S/T, Y, Lipid, Dual) • (two kinds: acidic and alkaline) • acidic phosphatase is an enzyme that catalyzes the hydrolysis of a number of phosphomonoesters at acid pH but not phosphodiesters. • Phosphoric monoester + H2O  Alcohol + Phosphoric acid. • alkaline phosphatase is an enzyme that catalyzes the hydrolysis of phosphomonoester at alkaline pH.

16. Glossary of molecule designations (cont.) • GAPs (RGSs, (Rho), (Ras), ARF) • (GTPase activating protein) • (growth-associate proteins) Promote the hydrolysis of bound GTP, thereby switching the G-protein to the inactive form. • GEFs ( (Rab), (Rho), (Ras), ARF) • (guanine nucleotide exchange factors) Family of proteins that facilitate the exchange of bound GDP or GTP on small G-proteins such as ras and rho and thus activate them. (act in the opposite way to GAPs.) • Adaptors/Regulators (Arrestins, G_beta, G_gamma, SH2) • a protein that holds multiple proteins in signaling complex. Adapter proteins do not have catalytic activity, nor do they directly activate effector proteins. They contain different docking sites for other proteins. They also provide a mean for crosstalk between pathways. Eg: Activation of Ras protein in insulin receptor signaling pathway (http://www.signaling-gateway.org/molecule/maps/insulin.html). IRS1, Grb2 are adapter proteins. GRB2 contains two SH3 domains, which binds to and activates Sos. Sos activates Ras. An adaptor protein acts as a platform to recruit other proteins to an activated receptor. • Channels/Transporters (Na+, K+, Ca-, Cl-) • channel is a passage through which substances move. Often refers to an ion channel which when activated allows the rapid movement of a particular ion across compartments. • transporters are membrane protein that assists the movement of another molecule across the cell membrane, or from one compartment of the cell to another.

18. Additional terminologies • protein recruiting another protein • a process whereby certain molecules are attracted (recruited) by another molecule to a particular site within the cell, often to form a complex which is a component of a pathway. For example the T-cell receptor (TCR) is a membrane associated receptor with extracellular portion which binds antigen (resulting in receptor activation) and intracelluar portion. Following activation, the intracellular portion has motifs which bind the SH2 domains of certain kinases. These kinases are said to be recruited by the activate TCR. Recruitment can also refer to intercellular communication, e.g. neutrophils may be recruited by cytokines released from other cells. • receptor desensitization: • process in which receptors are modified so that they no longer transduce a signal even if stimulus is still present. Result is attenuation of signaling. • second messenger