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Signal networks and pathways. Chitta Baral Arizona State University. Goal: Decoding the cell and …. Ultimate goal Decoding the cell (understand what is happening inside the cell) Control cell behavior It involves Accurate description of cellular biochemistry that allows

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signal networks and pathways

Signal networks and pathways

Chitta Baral

Arizona State University

goal decoding the cell and
Goal: Decoding the cell and …
  • Ultimate goal
    • Decoding the cell (understand what is happening inside the cell)
    • Control cell behavior
  • It involves
    • Accurate description of cellular biochemistry that allows
      • Explanation of particular cell behaviors and phenotypes (such as proliferation, cell migration, cell death, etc.)
      • Prediction of future behavior
      • Planning interactions with the cell to control the cell behavior
biochemistry network of interactions
Biochemistry, network of interactions
  • Relation between various molecules is often expressed using network of interactions (called Biochemical networks)
  • Three kinds of biochemical networks
    • Metabolic networks
      • Represent the chemical transformation between metabolites
      • Example: Glycolysis (breakdown of glucose)
    • Signal networks (also called protein networks)
      • Representing protein-protein interactions
    • Gene networks
      • Representing relationship between genes that encode the impact of the expression level of one gene on another
  • Pathways: Specific series of interaction in a network
g proteins
G proteins
  • 1994 Nobel prize. Discovery of G-protein coupled receptors and their role in signal transduction. Gilman, Alfred G. and Rodbell, Martin.
  • 43,409 articles in Medline that mention G proteins.
  • 1. Basic facts about G proteins
    • Each G-protein consists of 3 sub-units: Ga, Gb, and Gg.
    • These sub-units can be together or separated.
    • Each G-protein has a binding site that can be occupied by either GDP or GTP.
    • A G-protein is said to be inactive when it is bound to GDP.
    • A G-protein is said to be active when it is bound to GTP.
cyclicamp camp pathway
cyclicAMP (cAMP) pathway
  • 2. Up regulation: When a ligand binds to a receptor in a cell membrane the effect is that
    • A. the receptor becomes activated
    • B. the nucleotide binding site on the G-protein is altered,
    • C. GTP replaces GDP,
    • D. GDP is released,
    • E. and Ga-GTP gets disassociated from GbGg.
    • F. Ga being active triggers the binding of Ga-GTP to a membrane bound adenylate cyclase molecule,
      • activating it for production of cyclicAMP (cAMP).
cyclicamp camp pathway8
cyclicAMP (cAMP) pathway
  • 3. Down regulation – when the ligand dissociates from the receptor the effects are
    • A. GTP is hydrolyzed by a GTPase activity on Ga
    • B. Ga-GTP becomes Ga-GDP,
    • C. and disassociates from adenylate cyclase molecule, making the later inactive.
    • D. Ga then reassociates with GbGg
    • E. CyclicAMP (in the cytoplasm) is then inactivated by the enzyme phosphodiesterase, which hydrolyzes it to AMP.
interference with camp
Interference with cAMP
  • A. Cholera toxin inhibits the GTPase activity of the G-proteins of Gs subfamily, thus impacting 3A.
  • B. The ras gene produces a G-protein that lacks GTPase activity, thus impacting 3A.
  • C. Pertussis toxin inactivates the process that downregulates adenylate cyclase activity with respect to G-proteins of the Gi subfamily, with a few exceptions such as Gz, thus impacting 3C.
  • D. G-proteins of the Gq subfamily are not modifiable by pertussis toxin or cholera toxin, thus nullifying A and C above.
a specific example of camp mediated regulation glycogen degradation
A specific example of CAMP mediated regulation – Glycogen degradation
  • In liver or muscle cells in presence of the ligand epinephrine hormone (also called adernalin) increase in the cAMP concentration (in the cytoplasm)
    • activates protein kinase,
    • active protein kinases then converts inactive phosphorylase kinase to active form by ATP dependent phosphorylation,
    • active phosphorylase kinase then phosphorylates (i.e., converts) less active phosphorylase-b to more active phosphorylase-a, and
    • phosphorylase-a then catalyzes the phosphorolytic cleavage of glycogen into molecules of glucose-1-phosphate. (i.e., glycogen breakdown happens.)
references for stuff so far
References (for stuff so far)
  • The world of cell 2nd ed. Becker, Deamer. Chapter 21. (Latest one is 5th ed, by Becker, Kleinsmith and Hardin; has a nice Cd-Rom with the book and explains signal transduction very well)
  • Biochemistry of signal transduction and regulation. G. Krauss. Sec 5.5.1
  • Look for signal transduction, pathways, signal pathways, G protein, biochemical networks etc.
reasoning about camp and glycogen degradation
Reasoning about cAMP and Glycogen degradation
  • Observation: cAMP concentration way above normal
    • Possible explanation: presence of Cholera toxin or Pertussis toxin
    • Planning: How to overcome it using drugs.
  • Predicting the impact of not having enough adernalin.
  • Observation: Lack of glycogen breakdown.
    • Explained by low cAMP concentration
      • Explained by G proteins not getting activated in adequate concentration
computer science ai challenges
Computer Science (AI) challenges
  • Represent signal networks
    • Such that we can reason with it
    • We can elaborate on it (add more details) without making wholesale changes
  • Reason with them
    • Explain observations.
    • Predict effect of particular actions.
    • Plan to make the cell behave a particular way.
analogy with current ai research
Analogy with current AI research
  • Goal: To represent effect of actions on the world, executability condition of actions, relation between objects in the world, etc.
  • An example:
    • Description D.
      • S1 Load causes loaded.
      • S2 Shoot causes ~ alive if loaded.
      • S3 Intially alive.
      • S4 Initially ~loaded.
    • Planning: D |= ~alive after X. X=Load;Shoot.
    • Explanation: {S1, S2, S3, ~alive after shoot} |= Initially loaded
    • Prediction:
      • D |= ~alive after Load? D |= loaded after Load?
home work 3 due feb 17 th 100 pts
Home work 3 (Due Feb 17th) – 100 pts
  • Describe a particular signal pathway.
    • Draw the figure.
    • Write in English similar to the slides
    • Write in English-like syntax. (such as in the previous slide and make up specific terms like `causes’ that you may need.)
    • Source (journal: Cellular signaling; signal transduction chapter in books on cell biology; etc.) 50% bonus if you use a journal instead of a book.
  • Activation
    • A process of (i) initiating a chemical or biochemical reaction (ii) converting an inactive component to a functionally active form.
  • Adenylate Cylase
    • The enzyme that catalyzes the synthesis of cyclic AMP (cAMP) from ATP,
    • ATP <--> cAMP + PP
  • Allosteric
    • Pertaining to the topologically distinct sites on a protein or an enzyme molecule.
  • AMP
    • An Adenosine 3'-monophosphate or Adenosine 5'-monophosphate nucleotide with the phosphate group linked to the carbon 3 (or 5 resp.) of the ribose.
  • Arrestin
    • Family of inhibitory proteins that bind to tyrosine-phosphorylated receptors, thereby blocking their interaction with G-proteins and effectively terminating the signaling.
glossary cont
Glossary (cont)
  • Channel Protein
    • Proteins that form water-filled pores or channels across the membrane and are responsible for transporting solutes across the membrane.
  • conformational change
    • change in the form differing in secondary or tertiary structure.
  • cyclic AMP (cAMP)
    • An abbreviation for adenosine 3',5'-monophosphate or adenosine 2',3' -monophosphate.
    • An important intracellular regulator or second messenger for a number of cellular processes in animals, bacteria, fungi and plants.
  • Effector molecule
    • Small, biologically active molecule that acts as a regulator to control the activity of a protein or an enzyme by binding to a specific region on the protein or enzyme.
  • Enzyme
    • Bioactive protein that catalyzes the biochemical reactions in the living cell.
  • GAPs (growth-associate proteins)
    • Promote the hydrolysis of bound GTP, thereby switching the G-protein to the inactive form.
  • GDP (Guanosine 5'-Diphosphate)
  • GEFs (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.)
glossary cont18
Glossary (cont.)
  • G-Protein
    • A GTP binding membrane protein that is capable of hydrolyzing GTP, activating membrane bound CAMP, and mediating a variety of signal transducing systems.
  • GRK: G-Protein receptor kinase
  • GTP: Guanosine 5'-Triphosphate
  • GTPase (Guanosine triphosphatase)
    • Enzyme that catalyzes the reaction GTP +H20 <---> Guanosine + Triphosphate
  • Guanine: A constituent base in nucleic acids.
  • Guanosine: A nucleoside and constitutent of nucleotides
  • Hydrolysis: Splitting of 1 molecule to 2 by incorporation of 1 water molecule.
  • Induction
    • An increase in the rate of enzyme synthesis due to the presence of substrate or inducer.
  • Inhibition
    • (i) reduction or prevention in the rate of enzymatic activity (ii) repression of physical or chemical activity.
  • Kinase
    • The enzyme that catlyzes the transfer of a phosphate group from one compound to another.
  • Nucleoside
    • A component of a nucleotide that consists of a nitrogenous base (purine or pyrimidine) linked to a pentose sugar (ribose or deoxyribose)
glossary cont19
Glossary (cont.)
  • Nucleotide: The basic building blocks of nucleic acids it consists of a nucleoside and a phosphate.
  • phosphatase (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.
  • phosphodiesterase
    • The enzyme that catlyzes the hydrolysis of phosphodiester bond in the polynucleotides or cyclic nucleotides.
  • PKA: Protein kinase A
  • Protein
    • A polymer of L-amino acids that folds into a conformation specified by the linear sequence of amino acids nd functions as an enzyme, a hormone, an antibody or a structural component of the cell.
  • Regulatory enzyme
    • The enzyme that possesses a regulatory site for binding effector molecules in addition to the catalytic binding site.
  • RGS (Regulators of G-Protein signalling)
    • RGS is a protein that can increase the GTPase activity by more than one order of magnitude.
  • Transport protein: A protein that mediates the entry of specific substances into a cell.