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Systems and Synthetic Biology

, Volume 8, Issue 1, pp 83–97 | Cite as

Death ligand concentration and the membrane proximal signaling module regulate the type 1/type 2 choice in apoptotic death signaling

  • Subhadip RaychaudhuriEmail author
  • Somkanya C. Raychaudhuri
Research Article

Abstract

Apoptotic death pathways are frequently activated by death ligand induction and subsequent activation of the membrane proximal signaling module. Death receptors cluster upon binding to death ligands, leading to formation of a membrane proximal death-inducing-signaling-complex (DISC). In this membrane proximal signalosome, initiator caspases (caspase 8) are processed resulting in activation of both type 1 and type 2 pathways of apoptosis signaling. How the type 1/type 2 choice is made is an important question in the systems biology of apoptosis signaling. In this study, we utilize a Monte Carlo based in silico approach to elucidate the role of membrane proximal signaling module in the type 1/type 2 choice of apoptosis signaling. Our results provide crucial mechanistic insights into the formation of DISC signalosome and caspase 8 activation. Increased concentration of death ligands was shown to correlate with increased type 1 activation. We also study the caspase 6 mediated system level feedback activation of apoptosis signaling and its role in the type 1/type 2 choice. Our results clarify the basis of cell-to-cell stochastic variability in apoptosis activation and ramifications of this issue is further discussed in the context of therapies for cancer and neurodegenerative disorders.

Keywords

Systems biology Caspase 6 Cancer Neurodegenerative disorders Monte Carlo Single cell apoptosis 

Supplementary material

11693_2013_9124_MOESM1_ESM.docx (115 kb)
Supplementary material 1 (DOCX 114 kb)

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Copyright information

© Springer Science+Business Media Dordrecht 2013

Authors and Affiliations

  • Subhadip Raychaudhuri
    • 1
    • 2
    Email author
  • Somkanya C. Raychaudhuri
    • 3
  1. 1.Indraprastha Institute of Information TechnologyDelhiIndia
  2. 2.Department of ChemistryUniversity of California, DavisDavisUSA
  3. 3.Department of Biomedical EngineeringUniversity of California, DavisDavisUSA

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