Research Project

Molecular Mechanism of Receptor Tyrosine Kinase Associated Pathogenesis

The essential and diverse roles of RTKs are evident from the various developmental abnormalities and cancers that occur due to gain-of-function RTK signaling. We work with membrane model systems composed of lipids and peptides corresponding to the transmembrane domain of wild type and mutant RTKs.

Receptor tyrosine kinases (RTKs) are single-pass membrane proteins with an extracellular ligand-binding domain, a helical hydrophobic transmembrane (TM) domain, and an intracellular kinase domain. The RTK family includes several subfamilies, such as the epidermal growth factor receptors (EGFRs or ErbBs) and the fibroblast growth factor receptors (FGFRs). All RTKs, with the exception of the insulin and the insulin-like growth factor receptors, exist in a monomer-dimer equilibrium. The dimer, which is stabilized upon ligand binding, is the signaling competent structure. The essential and diverse roles of RTKs are evident from the various developmental abnormalities and cancers that occur due to gain-of-function RTK signaling.

Receptor concentration

Receptor concentration

Many questions of interest pertain to the thermodynamics of the dimerization process. These include the following: What are the effects of protein expression level and ligand concentration? What is the “correct” dimerization energy for normal RTK signaling? How much excess dimerization energy is required for persistent activation of the receptors and, therefore, for induction of pathologies?

To answer these questions, we have been working with membrane model systems composed of lipids and peptides corresponding to the transmembrane domain of wild type and mutant RTKs. We are also currently using traditional cell and molecular biology techniques to develop a new approach to quantitatively measure the difference in dimerization, activation and signaling in cells between wild type and mutant receptors. This work is allowing us to directly correlate receptor dimerization in the plasma membrane with receptor autophosphorylation levels, and will eventually allow us to develop a comprehensive model of unregulated cell signaling by RTKs.

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