Diversity in Dimerization Topologies Enables Differential Control of Receptor Tyrosine Kinase Phosphorylation Dynamics

• DOI: 10.1007/s12195-013-0303-x
• Publication Date: 2013-10-08T17:12:55Z
• Authors: Calixte S. Monast; Nabil Mehta; Matthew J. Lazzara
• Keywords: 0301 basic medicine; 03 medical and health sciences

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.