Download Representation of and Reasoning with signal networks

Representation of and Reasoning
with signal networks
Chitta Baral
Arizona State University
Existing terminologies
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Actions: when they occur they often change the world.
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Fluents: property of the world.
Situations: refers to time moments.
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Initial situation: refers to the initial moment.
Current situation: refers to the current moment
s0 , [ ]
sc, snow,
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.
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Eg. Loaded, alive, active
s, s1, s2, [a1, a2, …, an], res(a,s)
States: a view of the world at a particular moment
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Eg. load, shoot, ligand coming in contact with a receptor
Load causes loaded
Shoot causes ~alive if loaded
Executable load if has_bullet
Always alive  ~dead
Observations: f at s
a occurs_at s
Hypothetical Queries: f after a1, …, an
Entailment: the relation |= in
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f after a1, …, an at s
f after a1, …, an at s
D,O |= Q.
Can we infer or conclude that Q is true from our knowledge D and observation O.
The Yale shooting example
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Domain description: D
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Observations: O
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Load causes loaded
Shoot causes ~alive if loaded
Executable load if has_bullet
Initially alive, has_bullet, ~ loaded
Prediction:
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(D, O) |= ~alive after shoot?
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(D,O) |= ~alive after load, shoot?
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{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.
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S0 = {alive, has_bullet, ~loaded} shoot {alive, has_bullet, ~loaded}
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.
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Eg. Find O2 such that (D, {initially alive} U O2) |= ~alive after shoot.
O2 = {initially loaded}
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).
Bio-chemical terminologies that can be
accommodated within existing notions
• Bind
• Release
• Modify: eg. Phosphorylate,
dephosphorylate
• Activate,Inhibit.
New concepts and terminologies –
representational challenges
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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).
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Activated may have different physical meanings
– A protein that is `regulatively’ activated can be `physically’ either phosphorylated
or dephosphorylated by that activation.
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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.
Graphical representation
(from http://www.afcs.org/cm2/)
Glossary of interactions
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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.)
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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.
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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).
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.
Chemical transformations (ref. Misra)
X2
X1
Reversible Reaction
X2
X1
X2
X1
X3
Divergence Branch Point:
Degradation processes of
X1 into X2 and X3 are
independent
X3
X1
X3
X1
X3
X2
Convergence Branch Point:
Degradation processes of
X1 into X2 and X3 are
independent
X2
Single splitting reaction
generating two products
X2 and X3, in stoichiometric
proportion.
Single synthetic reaction
involving two source
components X1 and X2, in
stoichiometric proportion.
Chemical transformations (cont.) – ref. Misra
X3
X4
X2
X1
The reaction between X1 and X2
requires coenzyme X3 which is
converted to X4
X3
X2
X1
The conversion of X1 into X2 is
modulated by X3
X3
X1
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X2
The conversion of X1 into X2 is
modulated by an inhibitor X3
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
Glossary of molecule designations
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Receptors (eg. GPCR, RTKs, Cytokine, Nuclear)
GTPases (Ga, Rho, Ras, rab)
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(Guanosine triphosphatase)
– Enzyme that catalyzes the reaction GTP +H20  Guanosine + Triphosphate
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Enzymes (A Cyclase, G cyclase, Lipases, Protease)
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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.
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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.
Glossary of molecule designations (cont.)
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GAPs (RGSs, (Rho), (Ras), ARF)
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GEFs ( (Rab), (Rho), (Ras), ARF)
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(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)
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(GTPase activating protein)
(growth-associate proteins) Promote the hydrolysis of bound GTP, thereby switching the Gprotein to the inactive form.
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.signalinggateway.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-)
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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.
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.
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second messenger