Amplification and oscillations in the FAK/Src kinase system during integrin signaling
Equipe de Recherche sur les Relations Matrice Extracellulaire-Cellules,Université de Cergy-Pontoise, 2 avenue A. Chauvin. BP 222, 95302 Cergy Pontoise Cedex, France. Journal of Theoretical Biology
(Impact Factor: 2.12).
02/2005; 232(2):235-48. DOI: 10.1016/j.jtbi.2004.08.010
Integrin signaling is a major pathway of cell adhesion to extracellular matrices that regulates many physiological cell behaviors such as cell proliferation, migration or differentiation and is implied in pathologies such as tumor invasion. In this paper, we focused on the molecular system formed by the two kinases FAK (focal adhesion kinase) and Src, which undergo auto- and co-activation during early steps of integrin signaling. The system is modelled using classical kinetic equations and yields a set of three nonlinear ordinary differential equations describing the dynamics of the different phosphorylation forms of FAK. Analytical and numerical analysis of these equations show that this system may in certain cases amplify incoming signals from the integrins. A quantitative condition is obtained, which indicates that the total FAK charge in the system acts as a critical mass that must be exceeded for amplification to be effective. Furthermore, we show that when FAK activity is lower than Src activity, spontaneous oscillations of FAK phosphorylation forms may appear. The oscillatory behavior is studied using bifurcation and stability diagrams. We finally discuss the significance of this behavior with respect to recent experimental results evidencing FAK dynamics.
Available from: Silja Wessler
- "The clustering of integrins leads to the rapid recruitment of FAK to the FA complex, where it is autophosphorylated on tyrosine 397 (Y397) . This leads to the recruitment and activation of Src family kinases, which, together with FAK, are central in the regulation of downstream signaling pathways that control cell spreading, cell movement and cell survival [34,35]. Phosphorylation of FAK at Y397 correlates with increased catalytic activity and appears to be important for the tyrosine phosphorylation of focal complex-associated proteins such as paxillin. "
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ABSTRACT: Highly dynamic integrin-based focal adhesions provide an important structural basis for anchoring the cellular actin cytoskeleton to the surrounding extracellular matrix. The human pathogen Helicobacter pylori (H. pylori) directly targets integrins with drastic consequences on the epithelial cell morphology and migration, which might contribute to the disruption of the gastric epithelium in vivo. In this review, we summarize the recent findings concerning the complex mechanism through which H. pylori interferes with host integrin signaling thereby deregulating focal adhesions and the actin cytoskeleton of motile epithelial cells.
Available from: utexas.edu
Available from: clincancerres.aacrjournals.org
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