Receptor tyrosine kinases (RTK) are evolutionarily conserved transmembrane proteins that, upon binding to extracellular ligands, initiate signaling cascades that ultimately determine a wide-spectrum of cellular functions, including differentiation, migration, survival, and cell death. Due to their fundamental roles in cellular functions, deregulation often causes diseases, such as cancer. The overall goal of the proposal is to elucidate the molecular basis of recognition/activation between hepatocyte growth factor (HGF) and its receptor MET receptor tyrosine kinase (MET RTK). In human, HGF and MET play pivotal roles in embryonic development, morphogenesis, tissue repair, and progression of malignancy. Over-expression of MET, for instance, has been found in a growing list of cancers such as lung cancer, colorectal cancer, and glioblastoma, among others. Importantly, increasing evidence suggests that HGF can confer tumor resistance to therapies, thus hampering our current anti-cancer effort. As a result, there is a major incentive to study the mechanistic basis of HGF/MET signaling in order to advance future cancer research and treatment. Using high resolution X-ray crystallography, cellular assays and other biophysical approaches (such as electron-microscopy), this proposal will aim to elucidate the molecular basis of HGF/MET recognition and activation, which will enrich our thinking of RTK signaling as well as facilitate therapeutic development against cancers. Specifically, my aims for this proposal are: 1) determination of the molecular basis of HGF-MET recognition; 2) in vivo and in vitro characterization of MET activation processes. Results from Aim 1 will reveal a novel ligand-receptor interaction mode that should aid in therapeutic development targeting the ligand-receptor interface. Results from Aim 2 will reveal how HGF binding triggers MET activation, a process that is unknown to date, and elucidation of which will direct future effort of MET inhibito design. Overall, the results from the studies should shed tremendous light on how to manipulate the system for fighting cancers.
The importance of MET receptor and Hepatocyte Growth Factor (HGF) signaling in malignancy has become increasingly clear. Overexpression of MET, for instance, carries poor prognosis and is important in tumor progression in lung cancer, colorectal cancer, and glioblastoma, among others, and HGF is capable of conferring tumor resistance to anti-cancer agents. Thus, studies on the fundamental signaling mechanism of HGF/MET will directly impact the future of cancer research and treatment.
|Chen, Po-Han; Unger, Vinzenz; He, Xiaolin (2015) Structure of Full-Length Human PDGFR? Bound to Its Activating Ligand PDGF-B as Determined by Negative-Stain Electron Microscopy. J Mol Biol 427:3921-34|