Representation%20of%20and%20Reasoning%20with%20signal%20networks

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Representation of and Reasoning with signal
networks

• Chitta Baral
• Arizona State University

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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, ,
  an at s
• Hypothetical Queries f after a1, , an f after
  a1, , an at s
• Entailment the relation in D,O Q.
• Can we infer or conclude that Q is true from our
  knowledge D and observation O.

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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

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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).

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Bio-chemical terminologies that can be
accommodated within existing notions

• Bind
• Release
• Modify eg. Phosphorylate, dephosphorylate
• Activate,Inhibit.

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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.

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

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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.

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Chemical transformations (ref. Misra)
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Chemical transformations (cont.) ref. Misra
The reaction between X1 and X2 requires coenzyme
X3 which is converted to X4
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An example of chemical transformations
Glycolysis (ref. Misra)
Glycogen
P_i
Glucose-1-P
Glucose
Phosphorylase a
Phosphoglucomutase
Glucokinase
Glucose-6-P
Phosphoglucose isomerase
Fructose-6-P
Phosphofructokinase
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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.

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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.o
  rg/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.

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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