Structural and Functional Insight Into the Glycosylation Impact Upon the HGF/c-Met Signaling Pathway

Abstract

Upon interactions with its specific ligand hepatocyte growth factor (HGF), the c-Met signal is relayed to series of downstream pathways, exerting essential biological roles. Dysregulation of the HGF-c-Met signaling pathway has been implicated in the onset, progression and metastasis of various cancers, making the HGF-c-Met axis a promising therapeutic target. Both c-Met and HGF undergo glycosylation, which appears to be biologically relevant to their function and structural integrity. Different types of glycoconjugates in the local cellular environment can also regulate HGF/c-Met signaling by distinct mechanisms. However, detailed knowledge pertaining to the glycosylation machinery of the HGF-c-Met axis as well as its potential applications in oncology research is yet to be established. This mini review highlights the significance of the HGFc-Met signaling pathway in physiological and pathological context, and discusses the molecular mechanisms by which affect the glycosylation of the HGF-c-Met axis. Owing to the crucial role played by glycosylation in the regulation of HGF/c-Met activity, better understanding of this less exploited field may contribute to the development of novel therapeutics targeting glycoepitopes.

Bone marrow mesenchymal stem cells in premature ovarian failure: Mechanisms and prospects

“…The receptor tyrosine kinase cMET is the specific receptor of HGF, which is a member of the transmembrane tyrosine kinase receptor superfamily and has independent phosphorylation activity ( 91 ). The high-affinity binding of HGF to cMET induces homodimerization and autophosphorylation of the cytoplasmic domain of cMET, and then activates HGF/cMET and downstream pathways such as the MAPK/ERK, PI3K, p-38, and the Akt/protein kinase B pathways, thereby promoting cell proliferation, invasion, survival, motility and angiogenesis ( 88 , 92 , 93 ). The HGF/cMET pathway plays an important role in the BMSCs homing.…”

A novel anti-lung cancer agent inhibits proliferation and epithelial–mesenchymal transition

“…For example, among the reported c-Met inhibitors, crizotinib and cabozantinib are approved for the treatment of nonsmall-cell lung cancer and medullary thyroid cancer. 22 – 29 To date, no selective c-Met kinase inhibitors have been approved for clinical use. Based on the inhibitory results from the ELISA kinase assay, chalcone-1,3,4-thiadiazole hybrid ZW97 selectively and potently inhibited c-Met kinase with an IC 50 of 27.96 nM.…”

Single-molecule imaging and molecular dynamics simulations reveal early activation of the MET receptorin situ

“…We modeled the missing residues (UniProt P08581-1 sequence numbering, 92-110, 151-155, 206-209, 302-311, 378-383, 398-406, 411-413, 628-633) with the MODELLER ( 56 ) implemented on UCSF Chimera ( 57 ). We added 8 A2 N-glycans (di-sialylated, bi-antennary complex-type N-glycans) in both models on experimentally determined N-glycosylation sites (UniProt P08581-1 sequence numbering, residue 45, 106, 149, 202, 399, 405, 607, 635) ( 58 ).…”