Model Status

This CellML model still contains the reaction element. We have been unable to recode this model to remove the reaction element because the published paper does not contain a quantitative model. Therefore this CellML model is a purely qualitative model it and contains no mathematical description of the pathways defined. All the rates and concentrations have been set to 1.0.

Signal Transduction Pathway

Cardiac hypertrophy describes an abnormal condition where the heart becomes enlarged. Under stresses such as high blood pressure, or reduced blood flow through the coronary arteries, the heart must work harder. Instead of dividing and increasing in number, individual cells grow larger and genes normally expressed in the embryonic ventricle are reexpressed. Initially this compensation is effective, but excessive hypertrophy can kill more cells, which increases the stress on the heart, causing surviving cells to grow even larger, which in turn leads to an ever accelerating cycle that can eventually result in heart failure. Cardiac hypertrophy can also cause diseases such as myocardial infarction and arrhythmia, and therefore it is important to try and better understand the molecular mechanisms underlying the development of this condition.

Fibroblast growth factors (FGFs) represent one of five classes of peptide growth factors. Several in vitro studies have shown that FGF-2 (one of the many members of the FGF family) induces cardiac hypertrophy, and in vivo studies have shown that FGF-2 is naturally produced by cardiac myocytes and non-myocytes in the heart, where it plays an autocrine or a paracrine role.

The binding of FGF-2 to it's receptor FGFR - a transmembrane receptor tyrosine kinase (RTK) - induces receptor dimerisation and autophosphorylation. These phosphorylated tyrosines act as binding sites for cytosolic proteins with Src homology (SH2) domains, such as growth factor receptor bound protein 2 (GRB2). GRB2, with Son of sevenless protein (SOS) bound to it, then binds to the RTK, which activates SOS. SOS is a guanine nucleotide exchange factor (GEF) which activates the low-molecular-weight GTPase Ras, by inducing it to release GDP and exchange it for GTP. GTPase activating proteins (GAPs) accelerate the intrinsic GTP hydrolytic activity of Ras, thereby promoting the formation of the inactive, GDP-bound form of Ras (see Figure 1 below). Active Ras triggers a cascade of protein phosphorylation involving mitogen-activated protein kinase kinase kinase (Raf), mitogen activated ERK activating kinase (MEK), and extracellular signal regulated kinase (ERK). Upon activation, the ERKs phosphorylate cytoplasmic targets and they also translocate to the nucleus where they stimulate gene expression through the activation of transcription factors.

Through the common component Ras, activated FGFR is able to initiate several distinct cascades of protein phosphorylation (MAP kinase cascades). Other effectors such as protein kinase C (PKC) and phosphatidylinositol 3-kinase (PI3K) can also interact with the autophosphorylated tyrosine sites on the receptor, and they can also act further downstream in the signalling pathway, as activated Ras protein can induce other distinct responses, as shown in Figure 2 below. It is likely that for a given stimulus, only a limited subset of all the possible interactions shown here actually occur. It has been suggested that the specific effect of a stimulus will depend on the complex combination of pathways activated, which in turn is influenced by the spatial and temporal abundance of relevant proteins in the cell.

The description of this signal transduction pathway was based on a paper by Hefti et al. (1997), which investigates signalling pathways in cardiac myocyte hypertrophy. They conclude that different stimuli initiate distinct signal transduction pathways and that these cascades may interact in a complex manner to determine a unique morphological or biochemical response in the onset of cardiac hypertrophy. The complete original paper reference is cited below:

Signaling Pathways in Cardiac Myocyte Hypertrophy, Martin A. Hefti, Beatrice A. Harder, Hans M. Eppenberger and Marcus C. Schaub, 1997, Journal of Molecular and Cellular Cardiology , 29, 2873-2892. (A PDF version of the article is available to subscribers on the Journal of Molecular and Cellular Cardiology website.)

Signal Transduction Pathway Diagram

Schematic diagram of a FGF-2 signalling cascade.

Schematic diagram showing several FGF-2 signalling pathways and how they interact to form a signalling network. FGF-2 binds to a receptor tyrosine kinase (RTK), and then various proteins containing Janus kinase 1 (Jak), or increases in intracellular calcium (Ca2+). Ras targets multiple effectors (listed above).

• hefti_harder_eppenberger_schaub_1997_version02.cellml