Biochemical basis for the functional switch that regulates hepatocyte growth factor receptor tyrosine kinase...

Ligand-induced dimerization of receptor tyrosine kinases (RTKs) modulates a system of linked biochemical reactions, sharply switching the RTK from a quiescent state to an active state that becomes phosphorylated and triggers intracellular signaling pathways. To improve our understanding of this molecular switch, we developed a quantitative model for hepatocyte growth factor receptor (c-MET) activation using parameters derived in large part from c-MET kinetic and thermodynamic experiments. Our model accurately produces the qualitative and quantitative dynamic features of c-MET phosphorylation observed in cells following ligand binding, including a rapid transient buildup of phosphorylated c-MET at high ligand concentrations. In addition, our model predicts a slow buildup of phosphorylated c-MET under conditions of reduced phosphatase activity and no extracellular agonist. Significantly, this predicted response is observed in cells treated with phosphatase inhibitors, further validating our model. Parameter sensitivity studies clearly show that synergistic oligomerization-dependent changes in c-MET kinetic, thermodynamic, and dephosphorylation properties result in the selective activation of the dimeric receptor, confirming that this model can be used to accurately evaluate the relative importance of linked biochemical reactions important for c-MET activation. Our model suggests that the functional differences observed between c-MET monomers and dimers may have incrementally evolved to optimize cell surface signaling responses.