HGFR

HGFR stands for hepatocyte growth factor receptor, also known as the MET receptor tyrosine kinase. It is a cell surface receptor that binds hepatocyte growth factor (HGF) and plays a central role in embryonic development, organ morphogenesis, tissue regeneration, and wound healing. In adults, HGFR signaling is tightly regulated but can become dysregulated in disease, particularly cancer, where it contributes to tumor growth, invasion, and metastasis.

HGFR is encoded by the MET gene. The receptor is synthesized as a single precursor that is proteolytically cleaved into an extracellular alpha subunit and a beta subunit that traverses the membrane. The extracellular region contains a sema domain, a PSI domain, and several immunoglobulin-like domains (IPTs) that mediate ligand binding. The intracellular portion contains a juxtamembrane region and a phosphotyrosine kinase domain. A juxtamembrane tyrosine (Y1003) is involved in ubiquitination and degradation of the receptor, providing a mechanism for downregulation.

Upon HGF binding, HGFR dimerizes and undergoes autophosphorylation on key tyrosine residues, including Y1234/Y1235 in the activation loop and Y1349/Y1356 in the multifunctional docking site. These phosphorylated sites recruit adaptor proteins such as GRB2, SHC, and PI3K, triggering downstream signaling pathways including PI3K-AKT, RAS-ERK/MAPK, STAT3, and SRC. This signaling governs cell proliferation, survival, migration, and morphogenesis. In cancer, HGFR signaling can be constitutively active through receptor amplification, activating mutations, or HGF overexpression, promoting tumorigenesis and resistance to therapies.

Targeting HGFR or the HGF-MET axis has become an area of clinical interest. MET inhibitors (for example, capmatinib and tepotinib) are approved for MET exon 14 skipping alterations in non-small cell lung cancer, with other agents and antibody-based approaches in development.