Within the receptor tyrosine kinase (RTK) super-family there is natural diversity in mechanisms leading to RTK dimerization, but the impact on receptor-mediated signaling is not well understood. Using parameters from studies of epidermal growth factor receptor (EGFR) and considering effects of ligand binding, receptor dimerization, and receptor phosphorylation and dephosphorylation, we developed computational models to compare the effects of dimerization through direct extracellular receptor–receptor contacts (receptor-mediated dimerization, RMD) or through indirect receptor–receptor interactions facilitated by an interposed bivalent ligand (ligand-mediated dimerization, LMD). We found that the LMD topology enables different and complex regulatory modes of signaling vs. RMD, and that this complexity depends upon differences in time scales for ligand binding, dimerization, and receptor dephosphorylation. Compared to RMD, the LMD topology: (1) Enables non-monotonic phosphorylation dynamic response to ligand binding; (2) favors an amplification process wherein a single receptor-ligand binding event produces more than two phosphorylated receptors within the time scale for receptor dephosphorylation; and (3) generates greater phosphorylation sensitivity to changes in receptor expression at sub-saturating ligand concentrations and to changes in preformed receptor dimer abundance. Thus, different dimerization mechanisms may allow RTKs to initiate signaling in very different ways, and our models provide a framework for exploring this complexity.
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This work was supported by grant IRG-78-002-30 from the American Cancer Society. The authors also thank Janine Buonato for help in reviewing the manuscript.
Conflict of interest
The authors declare no conflicts of interest.
Associate Editor William H. Guilford oversaw the review of this article.
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Figure S1: Amplification and dimer uncoupling. (A and B) The steady-state ratio of the number of phosphorylated receptors to the number of bound ligands (pR/L b) was calculated as a function of ligand concentration (L) for the indicated values of the dephosphorylation rate constant (k dp) with the (A) ligand-mediated dimerization (LMD) and (B) receptor-mediated dimerization (RMD) models. These calculations were made with a receptor dimer uncoupling rate constant 105-fold lower than the base value.
Figure S2: Qualitative comparison of model to published data. The percent of total receptor that is phosphorylated (pR) was calculated as a function of time for the indicated ligand concentrations (L) with the ligand-mediated dimerization (LMD) model. To match the experimental conditions described in the Discussion section, we set k L,f = 5 × 101 μM−1min−1, an experimentally measured value, and k L,r such that K D,NGF was equal to the experimentally measured value of 10−10 M. The 20 min time point from the experiment is indicated by the dashed vertical line.
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Monast, C.S., Mehta, N. & Lazzara, M.J. Diversity in Dimerization Topologies Enables Differential Control of Receptor Tyrosine Kinase Phosphorylation Dynamics. Cel. Mol. Bioeng. 7, 86–98 (2014). https://doi.org/10.1007/s12195-013-0303-x
- Epidermal growth factor receptor (EGFR)
- Tropomyosin-related kinase A (TrkA)
- Time scale
- Ligand binding