Exemplary Introduction Draft 5
Contents
Introduction
Background and Hypothesis
The paper, Cell Surface Receptors for signal Transduction and Ligand Transport: A Design Principles Study by Harish Shankaran, Haluk Resat, and H. Steven Wiley, takes a mathematical modeling approach to understanding the dynamics of cell receptor systems. For their analysis, the authors selected four unique cellular receptor systems for which kinetic parameters had been measured in previous studies. The selected systems are EGFR, epidermal growth factor receptor, LDLR, low-density lipoprotein receptor, TfR, transferrin receptor, and VtgR, vitellogenin receptor.[1] EGFR is a signaling receptor system that is often seen to be overactive in cancers, and consequently inhibiting this receptor system can be beneficial in slowing or even stopping cancer growth.[2] LDLR is a cargo receptor system primarily linked to the transport of cholesterol.[3] TfR is also a cargo receptor system except its primary function is the cellular uptake of iron. [4] Finally, the VtgR system, which belongs to the same gene family as the LDLR system, acts as an importer of Vitellogenin in oocytes, female egg cells in oviparous animals. After being internalized, the Vitellogenin molecule is broken up to create various nutrient molecules for the prospective embryo.[5] These receptor systems perform their designated operations through the process of receptor mediated endocytosis which is depicted in the following diagram.[6]
1. Receptors (blue) bond with ligands (yellow).
2. A deep pocket forms in the cell wall, surrounding the receptor-ligand complexes.
3. The pocket pinches together, successfully internalizing the complexes.
4. Receptors and ligands dissociate, and the internalized cell wall begins to pinch together separating the two.
5. Receptors and ligands are separated from eachother. Receptors are sent back to the cell surface while the ligands are sent to the lysosomes, Golgi complex, or nucleus.
6. Pocket containting now free receptors merges with the cell wall, returning the receptors to the surface. [8]
Due to the general commonality of the process of receptor mediated endocytosis, the same mathematical model can be applied to all four selected receptor systems, provided that the correct kinetic parameters are used for each. If nondimensionalized, the differential modeling equations can be expressed in terms of two new parameters, the specific avidity and the partition coefficient. These two new parameters are functions of the original kinetic parameters defined for the modeled process. Specific avidity describes the system's ability to form receptor ligand complexes while the partition coefficient is a measure of consumption, the system's ability to internalized receptor-ligand complexes. The paper then hypothesizes that, by parameter manipulation, the selected receptor systems may be classified as avidity controlled, consumption controlled, or a combination of the two which will in turn all them to partially, if not completely, distinguish the receptor systems from one another.[1]
Significance
The authors undertook the analysis of these selected systems, first to better understand how, at the system level, a cell can adjust its kinetic parameters to control function[9], and secondly, they wished to highlight this concept of using a systems approach rather than a molecular approach to understanding cell function, a method they predict can have more diverse applications within the field of systems biology. Additionally, the results presented in the paper concerning identification of receptor systems through responsiveness to parameter variation could potentially be a useful tool when distinguishing cellular receptor systems.[1]
Brief Results and Model Extension
- to be included in final paper
References
- ↑ 1.0 1.1 1.2 Shankaran H, Resat H, Wiley HS (2007) Cell surface receptors for signal transduction and ligand transport: A design principles study. PLoS Comput Biol 3(6): e101.doi:10.1371/journal.pcbi.0030101
- ↑ Herbst,R. Review of epidermal growth factor receptor biology, International Journal of Radiation Oncology*Biology*Physics, Volume 59, Issue 2, Supplement, June 2004, Pages S21-S26, ISSN 0360-3016, 10.1016/j.ijrobp.2003.11.041. http://www.sciencedirect.com/science/article/pii/S0360301604003311
- ↑ Schneider, W J & Nimpf, J. (2003). LDL receptor relatives at the crossroad of endocytosis and signaling. Cellular and molecular life sciences : CMLS, 60. Retreived from http://www.biomedsearch.com/nih/LDL-receptor-relatives-at-crossroad/12827279.html
- ↑ Aisen P., Enns C., Wessling-Resnick M., Chemistry and biology of eukaryotic iron metabolism, The International Journal of Biochemistry & Cell Biology, Volume 33, Issue 10, October 2001, Pages 940-959, ISSN 1357-2725, 10.1016/S1357-2725(01)00063-2. http://www.sciencedirect.com/science/article/pii/S1357272501000632
- ↑ Li A, Sdavisam M, Ding JL (2003) Receptor-ligand interaction between vitellogenin receptor (VTGr) and vitellogenin (VTG), implications on low-density lipoprotein receptor and apolipoprotein B/E. The first three ligand-binding repeats of VTGr interact with the amino-terminal region of VTG. J Biol Chem278: 2799–2806. http://www.ncbi.nlm.nih.gov/pubmed/12429745
- ↑ Mukherjee S, Ghosh RN, Maxfield FR (1997) Endocytosis. Physiol Rev 77: 759–803.
- ↑ Luis Sanchez del-Campo, Montenegro M., Saez-Ayala M., Fernández-Pérez M. , Cabezas-Herrera J., Rodriguez-Lopez J.(2013). Cellular and Molecular Mechanisms of Methotrexate Resistance in Melanoma, Melanoma - From Early Detection to Treatment, Dr. Ht Duc (Ed.), ISBN: 978-953-51-0961-7, InTech, DOI: 10.5772/52414. Available from: http://www.intechopen.com/books/melanoma-from-early-detection-to-treatment/cellular-and-molecular-mechanisms-of-methotrexate-resistance-in-melanoma
- ↑ Bartholomew, E. F., & Martini, F. H. (2007). Essentials of anatomy & physiology. (4th ed.). San Francisco: Pearson Education Inc.
- ↑ Kitano H. (2002). Systems Biology: A Brief Overview. Science, Vol. 295, No. 5560. (01 March 2002), pp. 1662-1664, doi:10.1126/science.1069492
