Starbuck, Wiley, Lauffenburger, 1990

Model Status

This is the original unchecked version of the model imported from the previous CellML model repository, 24-Jan-2006.

Model Structure

Growth factors are a class of peptide hormones which are secreted locally from one cell and induce cell division or mitogenesis in other cells. Mitogenesis is initiated when growth factors bind to specific receptor-kinases on the cell surface, triggering a signal transduction pathway involving reversible protein phosphorylation by kinases and phosphatases.

In this 1990 study, Starbuck et al. propose that growth factor receptors are responsible for triggering the signal transduction cascade by receiving an extracellular signal (the specific growth factor molecules), and converting this stimulus into the cascade via activation of the receptor kinase and subsequent protein phosphorylation and activation. In addition, the receptor kinase is also able to phosphorylate other key proteins in the signal pathway. The authors argue that a quantitative understanding of the receptor dynamics is essential for the understanding of the control of mammalian cell growth.

To this end they develop a mathematical model of epidermal growth factor binding and trafficking dynamics in fibroblasts. The figure below illustrates the surface and intracellular events which are included in the mathematical model. The ligand (Lo) binds to its receptor on the cell surface (Rs) to form a ligand-receptor complex (Cs). One of two possible pathways can then be taken:

  • In the first pathway, the ligand-receptor complex migrates in the plane of the cell surface membrane to cluster in specialised regions of the membrane called clathrin-coated pits. Here, the complexes bind to the coated-pit proteins (Ps) to form ternary complexes (Ts), which are then internalised (Ti).

  • In the second pathway, the ligand-receptor complex is internalised as it is, without forming a ternary complex with pit-proteins (Cic).

After ternary complexes are internalised, the acidic environment of the endosome enhances receptor-ligand dissociation, firstly to form free complexes (Cii) and then further degradation to form free receptors (Rii) and free ligand (Lii). If Rii and/or Cii migrate into the endosomal tubules, they get recycled back to the cell surface membrane for further binding and trafficking. The fate of receptors (Ric) and complexes (Cic) from the smooth pit pathway is not as well understood, but recycling is also assumed to occur.

The mathematical model to describe this process consists of a series of kinetic equations which describe the binding, internalisation and recycling of epidermal growth factor and its receptor, together with a simple expression which relates the dependence of the cell cycle progression on the receptor dynamics.

The complete original paper reference is cited below:

Epidermal Growth Factor Binding and Trafficking Dynamics in Fibroblasts: Relationship to Cell Proliferation, Cindy Starbuck, H. Steven Wiley, and Douglas A. Lauffenburger, 1990, Chemical Engineering Science , 45, 2367-2373. (A PDF version of the article is available on the Chemical Engineering Science website.)

A schematic diagram of the processes which take place in the response of mammalian cells to epidermal growth factor.
Derived from workspace Starbuck, Wiley, Lauffenburger, 1990 at changeset 2e0f2403ee99.
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