Bioengineering Models of Cell Signaling

1
Bioengineering Models of Cell Signaling

• Anand R. Asthagiri and Douglas A. Lauffenburger
• Discussion led by
• Ronojoy Ghosh
• Journal Club on Modeling Biological Networks
• February 6, 2002

2
Introduction

• Ubiquitous in regulating biological processes
• Development, tissue function, immune response
• Cell signaling
• Read Translate React Write
• Aberrations
• Autoimmune diseases, cancer development
• Target for disease therapy
• Quantitative insight

3
Signal Transduction Mechanism

• Large number of molecules and interaction
• Example read functionality
• ECM extracellular matrix

4
Signal Transduction Mechanism

• Translation cascade (simplified)
• Involves numerous intracellular molecules
• Lipids, proteins

5
Signal Transduction Mechanism

• Different functional domains
• Mediate physical interaction
• Phosphorylation
• Protein docking
• Catalyze reactions
• Lipid cleavage

6
Interconnectivity

• Multiple domains
• Branch points
• Reconvergence further downstream
• Different stimulus-sensor pairs share common
  machinery
• Multiple stimuli ? interconnected signaling
  network ? multiple cell functions

7
Signaling Biochemistry

• Information flow metrics
• Degree of phosphorylation, catalytic activity
• Steady-state efficiency
• Local sensitivity factor
• Global sensitivity
• Hill coefficient, ?
• ? gt 1, ultrasensitive response

8
Signaling Biochemistry

• Other stimulus-response relations
• Biphasic
• Triphasic (three different response states)
• Example Xenopus blastula cells, different number
  of bound receptors, different transcription
• Stochastic analysis
• Random variations can influence decisions
• Insight transient analysis required

9
Signaling Biochemistry

• Transient signals
• Cyclical and noncyclical
• Adaptation signal returns to base (unstimulated)
  steady-state level

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Signaling Biochemistry

• Noncyclical signals
• Transient change of rate influences downstream
  targets in case of complete adaptation
• Same time scale E. coli run and tumble
• Delayed action ERK2 activation 15 min affects
  DNA synthesis 15 hr later
• Integral of pulse-signal is good information
  metric

11
Signaling Biochemistry

• Cyclical transient signals
• Oscillations of cytosolic free calcium ions
• Signal frequency changes with agonist through
  positive and negative feedback
• Frequency encoded cell response information
• Cell cycle related cyclins and cyclin-dependent
  kinases
• Need mathematical modeling framework for dynamic
  analysis

12
Signaling Biophysics

• Spatial differentiation
• Extracellular e.g.. track for immune response
• Intracellular proper localization of proteins
• Extracellular environment
• ECM dynamic space
• Regulated location of extracellular cues
• Viscosity change, scaffolds, blocking molecules
• Active vesicular transport Wingless in
  Drosophila
• Autocrine cell secreted ligands, system
  conditions regulate group of cells receiving
  signal

13
Signaling Biophysics

• Intracellular localization
• Membrane localized reactions
• Membrane associated proteins
• Reaction kinetics and diffusion rates determine
  localized substrate depletion
• Regulates signal transfer rates and components
• Compartmentalization
• Active transport of signaling molecules to
  intracellular vesicles GFR-mediated signaling

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Signaling Biophysics

• Localization changes reaction dynamics
• Local concentrations change Hill coefficient
• Localization could introduce cross-talk
• Signaling fidelity preserved through scaffold
  proteins hard-wiring specific pathways
• End-point activity localization AKAP

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Mechanical Forces

• Response to external loads
• Example mechanical resistance of cartilages
• Examples shear stress affects cells lining blood
  vessel walls
• Mechanoreceptors at cell membrane
• Binds to both ECM proteins and cytoskeleton
• Mechanism
• Geometrical reconfiguration
• Alter reaction kinetics

16
Mechanical Forces

• Mechanism
• Change enzyme functionality
• Physiochemical signaling works both ways
• Chemical signals converted to mechanical force
  through cytoskeleton
• Local ECM proteins modified

17
Conclusion

• Network modeling hard!!
• Hierarchical design
• Process modules
• Reaction kinetics differential equations
• Higher level
• Boolean or fuzzy logic
• Next example of computational analysis
• Asthagiri AR, Lauffenburger DA. A computational
  study of feedback effects on signal dynamics in a
  mitogen-activated protein kinase (MAPK) pathway
  model. Biotechnol. Prog. 2001, 17, 227-239