Signal integration in the TGFb pathway

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Signal integration in the TGF-b pathway

• Ronald Jansen
• Jose Vilar
• Work in progress
• March 30, 2004

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Background Significance

• TGF-? fosters tissue growth and morphogenesis
  during embryogenesis
• In the adult, TGF-? delivers cytostatic and cell
  death signals, helping to maintain tissue
  homeostasis
• Loss of responsiveness to TGF-? contributes to
  tumor development
• Cancer cells that avert TGF?-mediated cytostasis
  may then use this factor with impunity to
  exacerbate their own proliferative, invasive, and
  metastatic behavior.

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Background Significance
Cytostatic signal
Loss of responsiveness
Growth-promoting signal
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Role reversal of TGF-b
(Joan Massagué)
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The TGF-b pathway in essence
(Joan Massagué)
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Canonical TGF-b pathway
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TGF-b family of ligands
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TGF-b family of ligands
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Receptor families
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Antagonists
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Receptor Smads (R-Smads)
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Receptor Smads (R-Smads)
Gene expression program 1
Gene expression program 2
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Aside representation of data
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Cell-type specific events
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Cell-specific responses to TGF-b

• List different cases

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Network of parallel pathways

• Potential for cross-talk among parallel
  signals?Signal integration
• Downstream consequences

50 ligand-receptor complexes
Gene expression program 1
Gene expression program 2
Smad1/5/8
Smad2/3
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Signal integration

• Multiple ligands present
• Sharing of pathway components
• Ligands
• Receptors
• R-Smads
• Co-Smad
• (I-Smad)
• Non-intuitive consequences ? Role reversal of
  TGF-b

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Modeling?

• Decompose complex network into simple subsystems
• Analyze subsystems
• Single-ligand model
• Two-ligand model

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Modeling results

• System with multiple signals
• Characteristic behaviors
• Additive
• Competitive
• System with single ligand
• Characteristic behaviors (ligand step change)
• Step response
• Transient response

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Single-ligand model
L

• Steady-state flux balancer fD gITIfD
  fD(L)

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Single-ligand model

• Degradation dominates dimerization r gITI

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Single-ligand model

• Dimerization dominates degradationr fD

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Single-ligand model simulation results
Degradation dominates dimerization
Step response
Transient response
Dimerization dominates degradation
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Single-ligand model summary

• 1st extremeDegradation dominates
  dimerizationgt Step response type
• 2nd extremeDimerization dominates
  degradationgt Transient response type
• Neither process dominatesgt Mixed response type

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Two-ligand model

• Steady-state flux balancer fD1 fD2
  gITIfDi fDi(Li)

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Two-ligand model

• Degradation dominates dimerization r gITI

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Two-ligand model

• Dimerization dominates degradationr fD1 fD2

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Two-ligand model simulation results
Degradation dominates dimerization
Additive signals
Competitive signals
Dimerization dominates degradation
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Two-ligand model summary

• 1st extremeDegradation dominates
  dimerizationgt Additive signals
• 2nd extremeDimerization dominates
  degradationgt Competitive signals
• Neither process dominatesgt Mixed response type

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Role reversal of TGF-b
TGF-b
BMP

• Dimerization dominates degradationr fD1 fD2
• Output ? fD1 fD2

TGF-b RII
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Role reversal of TGF-b
TGF-b
BMP

• Dimerization dominates degradationr fD1 fD2
• Output ? fD1 fD2

TGF-b RII
Mutation in kinase domain of TGF-b RII
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Role reversal of TGF-b
Sum of outputs
Wild-type
Sum of outputs
Mutation in kinase domain of TGF-b RII
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Role reversal of TGF-b

• Previous case studies mutations that affect
  downstream gene expression network
• Previous cases do not explain how loss of TGF-b
  responsiveness, because of mutations in upstream
  pathway, can be reversed (for instance, receptor
  mutations common in colon cancer)
• Our model provides a straightforward explanation
  for role reversal

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Future directions

• Signal integration in other signaling systems

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Future directions

• Drugs targeting TGF-b pathways
• Metastatic vs. normal cells

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Summary

• Potential mechanism for metastasis when mutations
  in upstream pathway occur