Tian, T., Plowman, S.J., Parton, R.G., Kloog, Y. and Hancock, J.F. (2010) Mathematical modeling of K-Ras nanocluster formation on the plasma membrane. Biophysical Journal, 99(2), pp. 534-543. (doi: 10.1016/j.bpj.2010.04.055)
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Abstract
K-Ras functions as a critical node in the mitogen-activated protein kinase (MAPK) pathway that regulates key cellular functions including proliferation, differentiation, and apoptosis. Following growth factor receptor activation K-Ras.GTP forms nanoclusters on the plasma membrane through interaction with the scaffold protein galectin-3. The generation of nanoclusters is essential for high fidelity signal transduction via the MAPK pathway. To explore the mechanisms underlying K-Ras.GTP nanocluster formation, we developed a mathematical model of K-Ras-galectin-3 interactions. We designed a computational method to calculate protein collision rates based on experimentally determined protein diffusion rates and diffusion mechanisms and used a genetic algorithm to search the values of key model parameters. The optimal estimated model parameters were validated using experimental data. The resulting model accurately replicates critical features of K-Ras nanoclustering, including a fixed ratio of clustered K-Ras.GTP to monomeric K-Ras.GTP that is independent of the concentration of K-Ras.GTP. The model reproduces experimental results showing that the cytosolic level of galectin-3 determines the magnitude of the K-Ras.GTP clustered fraction and illustrates that nanoclustering is regulated by key nonequilibrium processes. Our kinetic model identifies a potential biophysical mechanism for K-Ras nanoclustering and suggests general principles that may be relevant for other plasma-membrane-localized proteins.
| Item Type: | Articles |
|---|---|
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Tian, Dr Tianhai |
| Authors: | Tian, T., Plowman, S.J., Parton, R.G., Kloog, Y., and Hancock, J.F. |
| Subjects: | Q Science > QA Mathematics |
| College/School: | College of Science and Engineering > School of Mathematics and Statistics > Mathematics |
| Journal Name: | Biophysical Journal |
| Journal Abbr.: | Biophys J. |
| ISSN: | 0006-3495 |
| ISSN (Online): | 1542-0086 |
| Published Online: | 20 July 2010 |
| Related URLs: |
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