Quantitative Analysis of the Rewiring of Signaling Pathways to Alter Cancer Cell Fate
Cancer occurs when signaling pathways become unregulated or constitutively activated inside a cell. For example, deregulation of the mitogen activated protein kinase (MAPK) pathway often leads to cancer by promoting uncontrolled cellular proliferation. Chimeric proteins can rewire these signal transduction pathways active in cancer cells by linking activation of the MAPK pathway to activation of the Fas apoptosis pathway, causing the input signal for cell proliferation to be redirected to induce cell death.
We present here a kinetic model demonstrating how these chimeric proteins can trigger apoptosis upon stimulation of the MAPK pathway. This model consists of ordinary differential equations using rate constants found in literature along with experimental data from previously published work. At a concentration of 1500 nM, the chimeric protein caused a 60% decrease in MAPK activation, causing the cell to transition from a proliferative state to an apoptotic state, validating previous experimental observations. Even at much lower concentrations (e.g. 24 nM), the apoptosis pathway is activated, so the model suggests that cell death may occur even without a direct suppression of the proliferation pathway.
Results and Conclusions
We have developed a quantitative model of caspase activation and its effect on the MAPK pathway in the presence of a chimeric protein, providing insight into a potential mechanism for reprogramming cancer cells.
KeywordsTyrosine kinases Biochemical simulation Cell signaling Kinetic modeling Reprogramming Cancer
List of Abbreviations
Epidermal growth factor
Epidermal growth factor receptor
Phosphorylated EGF ligand and EGFR complex with Csp8 bound
Phosphorylated EGF ligand and EGFR complex
Phosphorylated EGF ligand and EGFR complex with PTD-DED bound
Fas-associated protein with death domain
Latent membrane protein 1
Ligand receptor complex
Mitogen-activated protein kinase
Multiplicity of infection
Nerve growth factor
- PI3 K-Akt
Phosphoinositide 3-kinase-RAC-alpha serine/threonine-protein kinase
Protein kinase C
Chimeric protein utilizing phosphotyrosine binding (PTB) domain and death-effecter domain (DED)
Receptor tyrosine kinases
Src homoloy 2 domain
Tobacco etch virus protease
The authors would like to thank to Dr. Satoshi Yamada and colleagues for supplying us with the equations and parameters for their model as well as Dr. Perry Howard for many helpful conversations, insights and direction. This work was supported by an NSERC URSA award (RS), NSERC Discovery Grants (RE and SMW), and the Canada Research Chairs program (SMW).
- 3.Pearson, G., et al. (2001). Mitogen-activated protein (MAP) kinase pathways: regulation and physiological functions. Endocrine Reviews, 22(2), 153–183.Google Scholar
- 21.Lauffenburger, D. A., & Linderman, J. J. (1993). Receptors: Models for binding, trafficking, and signalling (p. 361). New York: Oxford University Press.Google Scholar