State of the structure address on MET receptor activation by HGF

By Edmond M. Linossi, Gabriella O. Estevam, Masaya Oshima, James Fraser1, Eric A. Collisson, Natalia Jura

1. University of California-San Francisco

See also

No results found.

Published on

Type

journal-article

Author

Edmond M. Linossi and Gabriella O. Estevam and Masaya Oshima and James S. Fraser and Eric A. Collisson and Natalia Jura

Citation

Linossi, E. M., Estevam, G. O., Oshima, M., Fraser, J. S., Collisson, E. A., & Jura, N. (2021). State of the structure address on MET receptor activation by HGF. Biochemical Society Transactions, 49(2), 645–661. https://doi.org/10.1042/bst20200394

Abstract

The MET receptor tyrosine kinase (RTK) and its cognate ligand hepatocyte growth factor (HGF) comprise a signaling axis essential for development, wound healing and tissue homeostasis. Aberrant HGF/MET signaling is a driver of many cancers and contributes to drug resistance to several approved therapeutics targeting other RTKs, making MET itself an important drug target. In RTKs, homeostatic receptor signaling is dependent on autoinhibition in the absence of ligand binding and orchestrated set of conformational changes induced by ligand-mediated receptor dimerization that result in activation of the intracellular kinase domains. A fundamental understanding of these mechanisms in the MET receptor remains incomplete, despite decades of research. This is due in part to the complex structure of the HGF ligand, which remains unknown in its full-length form, and a lack of high-resolution structures of the complete MET extracellular portion in an apo or ligand-bound state. A current view of HGF-dependent MET activation has evolved from biochemical and structural studies of HGF and MET fragments and here we review what these findings have thus far revealed.

DOI