RTKs control cell growth, proliferation, and differentiation. Aberrant RTK signaling is at the heart of many diseases connected to development and growth. For example, epidermal growth factor receptor (EGFR or ErbB1) is linked to tumorigenesis, most notably in lung cancer, for which several FDA-approved EGFR inhibitors have been developed.
The challenge is that receptor structures and activation mechanisms are difficult to resolve because of their intrinsic architecture. All proteins in the RTK family share three structural features, including a ligand-binding ECD, a single-pass transmembrane α-helix (TM), and an ICD with a kinase enzyme. The linkers between these domains are flexible. This conformational flexibility has frustrated efforts to resolve structures of the full-length protein. At the same time, the regions of the protein that immediately flank the membrane (e.g., the intracellular juxtamembrane domain [JM]) are conformationally coupled through the membrane and are integral to protein function. Work in my lab aimed at resolving the assembly of RTKs into dimeric and multimeric species before and after ligand binding. These interactions regulate function and are important in the development of new drugs. Our current focus is on EphA2 and disease-related mutants of EGFR
Shi, X., Hapiak, V., Zheng, J., Muller-Greven, J., Bowman, D., Lingerak, R., Buck, M., Wang, B.-C., and Smith, A. W. (2017) A role of the SAM domain in EphA2 receptor activation, Scientific Reports 7, 45084.
Huang, Y., Bharill, S., Karandur, D., Peterson, S. M., Marita, M., Shi, X., Kaliszewski, M. J., Smith, A. W.*, Isacoff, E. Y.*, Kuriyan, J.*, (2016) Molecular Basis for Multimerization in the Activation of the Epidermal Growth Factor Receptor. eLife, 5, e14107. *Joint corresponding authors
Endres, N. F.*, Das, R.*, Smith, A. W.*, Arkhipov, A., Kovacs, E., Huang, Y., Pelton, J.G., Shan, Y., Shaw, D.E., Wemmer, D.E., Groves, J.T., Kuriyan, J.(2013) Conformational Coupling across the Plasma Membrane in Activation of the EGF Receptor. Cell 152, 543-546. *Equal Contribution