Article

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: 2.3). 02/2005; 232(2):235-48. DOI: 10.1016/j.jtbi.2004.08.010
Source: PubMed

ABSTRACT 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.

Download full-text

Full-text

Available from: Geoffrey Caron-Lormier, Jun 22, 2015
0 Followers
 · 
100 Views
  • Source
    [Show abstract] [Hide abstract]
    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.
    Cell Communication and Signaling 02/2008; 6:2. DOI:10.1186/1478-811X-6-2 · 4.67 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Focal adhesion kinase (FAK) is a non-receptor protein tyrosine kinase that is expressed in the cytoplasm of many cell types, including osteoblasts. FAK is activated when integrin receptors interact with proteins of the extracellular matrix and is then recruited to focal adhesion complexes. The presence of kinase in these structures is strictly associated with its function in cell processes such as adhesion, migration and proliferation. FAK-deficient cells spread more slowly and exhibit reduced migration. Kinase activates various intracellular signaling pathways, including those leading to cell differentiation. When regulating mitogen activating protein kinase (MAPK), FAK influences in vitro cell maturation and differentiation into osteoblasts. The expression of genes characteristic for osteoblast phenotype, such as Runx2 and Osterix, is stimulated by FAK activation, whereas FAK gene deficiency prevents differentiation into osteoblastic cells. This review describes the role that FAK plays in cell biology, with particular attention to osteoblasts.
    Postepy Biologii Komorki 01/2009; 36(4):707-721. · 0.20 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Adhesion of epithelial cells to basement membranes (BM) occurs through two major structures: actin-associated focal contacts and keratin-associated hemidesmosomes, both of which form on laminin-332 (Ln-332). In epithelial-derived cancer cells, additional actin-linked structures with putative adhesive properties, invadopodia, are frequently present and mediate BM degradation. A recent study proposed that BM invasion requires a proper combination of focal contacts and invadopodia for invading cells to gain traction through degraded BM, and suggested that these structures may compete for common molecular components such as Src kinase. In this study, we tested the role of the Ln-332 in regulating invadopodia in 804G rat bladder carcinoma cells, a cell line that secretes Ln-332 and forms all three types of adhesions. Expression of shRNA to Ln-332 gamma2 chain (gamma2-kd) led to increased numbers of invadopodia and enhanced extracellular matrix degradation. Replating gamma2-kd cells on Ln-332 or collagen-I fully recovered cell spreading and inhibition of invadopodia. Inhibition of alpha3 or beta1, but not alpha6 or beta4, phenocopied the effect of gamma2-kd, suggesting that alpha3beta1-mediated focal contacts, rather than alpha6beta4-mediated hemidesmosome pathways, intersect with invadopodia regulation. gamma2-kd cells exhibited alterations in focal contact-type structures and in activation of focal adhesion kinase (FAK) and Src kinase. Inhibition of FAK also increased invadopodia number, which was reversible with Src inhibition. These data are consistent with a model whereby actin-based adhesions can limit the availability of active Src that is capable of invadopodia initiation and identifies Ln-332-beta1 interactions as a potent upstream regulator that limits cell invasion.
    Journal of Cellular Physiology 01/2009; 223(1):134-42. DOI:10.1002/jcp.22018 · 3.87 Impact Factor