Mathematical modeling of K-Ras nanocluster formation on the plasma membrane

Tian, Tianhai, Plowman, Sarah J., Parton, Robert G., Kloog, Yoel and Hancock, John F. (2010) Mathematical modeling of K-Ras nanocluster formation on the plasma membrane. Biophysical Journal, 99 2: 534-543. doi:10.1016/j.bpj.2010.04.055

Author Tian, Tianhai
Plowman, Sarah J.
Parton, Robert G.
Kloog, Yoel
Hancock, John F.
Title Mathematical modeling of K-Ras nanocluster formation on the plasma membrane
Journal name Biophysical Journal   Check publisher's open access policy
ISSN 0006-3495
Publication date 2010-07-21
Sub-type Article (original research)
DOI 10.1016/j.bpj.2010.04.055
Volume 99
Issue 2
Start page 534
End page 543
Total pages 20
Place of publication St. Louis, MO, United States
Publisher Cell Press
Collection year 2011
Language eng
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. Copyright © 2010 Biophysical Society Published by Elsevier Inc.
Keyword Cell membrane
Computer simulation
Enzyme activation
Galectin 3
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2011 Collection
Institute for Molecular Bioscience - Publications
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Citation counts: TR Web of Science Citation Count  Cited 22 times in Thomson Reuters Web of Science Article | Citations
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Created: Sun, 08 Aug 2010, 00:07:08 EST