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 HGF-c-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.
Highlights
Since the discovery of c-Met and its high-affinity cognate ligand hepatocyte growth factor (HGF) in 1980s (Nakamura and Mizuno, 2010), decades of research have disclosed that c-Met and HGF play significant roles in embryonic development, tissue regeneration and cell motility (Sakai et al, 2015; De Silva et al, 2017)
The heparin-binding site of HGF appears to be formed, partly if not all, by the N-terminal hairpin loop and the K2 domain. As those same domains are critical for c-Met binding and HGF/c-Met signaling, it has been implicated that heparin and its analogs heparan sulfate may act as co-receptors of HGF by stabilizing the HGF-c-Met complex, which makes the engagement between HGF and c-Met kinetically more favorable (Holmes et al, 2007)
Upon HGF-induced activation, aberrant c-Met activation facilitates enhanced tumor cell growth, angiogenesis and invasion in cancer, which is overall associated with poorer survival, suggesting that the c-Met/HGF axis is a promising therapeutic target against malignancies
Summary
Since the discovery of c-Met and its high-affinity cognate ligand HGF in 1980s (Nakamura and Mizuno, 2010), decades of research have disclosed that c-Met and HGF play significant roles in embryonic development, tissue regeneration and cell motility (Sakai et al, 2015; De Silva et al, 2017). The heparin-binding site of HGF appears to be formed, partly if not all, by the N-terminal hairpin loop and the K2 domain As those same domains are critical for c-Met binding and HGF/c-Met signaling, it has been implicated that heparin and its analogs heparan sulfate may act as co-receptors of HGF by stabilizing the HGF-c-Met complex, which makes the engagement between HGF and c-Met kinetically more favorable (Holmes et al, 2007). Both pro-HGF and pro-c-Met undergo post-translational modifications, including glycosylation, disulfide bonds formation and proteolytic cleavage, to generate their mature forms. HGF as well as their associated biological roles still remains largely unknown
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