Activation of hepatocyte growth factor by proteolytic conversion of a single chain form to a heterodimer.

Naka, Daiji; Ishii, Takuro; Yoshiyama, Yoshiko; Miyazawa, Keiji; Hara, Hiroto; Hishida, Tadashi; Kidamura, N

doi:10.1016/s0021-9258(19)88673-8

Cited by 178 publications

(22 citation statements)

References 28 publications

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“…One of these antibodies, anti-Met 5D5, bound Met and inhibited HGF binding. The Fab fragment of anti-Met 5D5 (anti-Met 5D5-HGF and scHGF (R494E) bind to the Sema domain HGF is secreted as an inactive single-chain precursor and is Fab) was shown to inhibit HGF-driven Met phosphorylation, cell proliferation, and tumor growth (R. Schwall, personal communi-cleaved by extracellular proteases into an ␣ and ␤ chain (Naka et al, 1992). The cleaved disulfide-linked ␣ and ␤ chains of HGF cation).…”

Section: The Sema Domain Is Necessary For Met Receptor Crosslinkingmentioning

confidence: 99%

The Sema domain of Met is necessary for receptor dimerization and activation

Stamos²,

2004

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Hepatocyte growth factor (HGF) binds the extracellular domain and activates the Met receptor to induce mitogenesis, morphogenesis, and motility. The extracellular domain of Met is comprised of Sema, PSI, and four IPT subdomains. We investigated the contribution of these subdomains to Met receptor dimerization. Our observations indicate that the Sema domain is necessary for dimerization in addition to HGF binding. Treatment of Met-overexpressing tumor cells with recombinant Sema in the presence or absence of HGF results in decreased Met-mediated signal transduction, cell motility, and migration, behaving in a manner similar to an antagonistic anti-Met Fab. These data suggest that the Sema domain of Met may not only represent a novel anticancer therapeutic target but also acts as a biotherapeutic itself.

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Section: The Sema Domain Is Necessary For Met Receptor Crosslinkingmentioning

confidence: 99%

The Sema domain of Met is necessary for receptor dimerization and activation

Stamos²,

2004

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“…It is believed to have a critical role in the development and regenerative processes of various organs (Boros and Miller 1995;Matsumoto and Nakamura 1996). HGF/SF is secreted as an inactive precursor, and normally it remains in this precursor form, probably associated with the extracellular matrix in the producing tissues (Naka et al 1992). To generate the biologically active HGF/SF, proteolytic conversion of the single-chain precursor form to the two-chain heterodimer active form is essential (Naka et al 1992).…”

mentioning

confidence: 99%

“…HGF/SF is secreted as an inactive precursor, and normally it remains in this precursor form, probably associated with the extracellular matrix in the producing tissues (Naka et al 1992). To generate the biologically active HGF/SF, proteolytic conversion of the single-chain precursor form to the two-chain heterodimer active form is essential (Naka et al 1992). This converting activity, designated as HGF activator (HGFA), was purified and its cDNA was cloned (Shimomura et al 1992;Miyazawa et al 1993).…”

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confidence: 99%

Distribution of Hepatocyte Growth Factor Activator Inhibitor Type 1 (HAI-1) in Human Tissues: Cellular Surface Localization of HAI-1 in Simple Columnar Epithelium and Its Modulated Expression in Injured and Regenerative Tissues

Kataoka

Suganuma

Shimomura

et al. 1999

J Histochem Cytochem.

108

135

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SUMMARYWe used a specific monoclonal antibody to human hepatocyte growth factor activator inhibitor type 1 (HAI-1) in immunohistochemical procedures to determine the distribution and localization of HAI-1 in human tissues. In normal adult tissues, HAI-1 was predominantly expressed in the simple columnar epithelium of the ducts, tubules, and mucosal surface of various organs. In all cases, HAI-1 was localized predominantly on the cellular lateral (or basolateral) surface. By contrast, hepatocytes, acinar cells, endocrine cells, stromal mesenchymal cells, and inflammatory cells were hardly stainable with the antibody, and stratified squamous epithelium showed only faint immunoreactivity on the surface of cells of the basal layer. In the gastrointestinal tract, the surface epithelium was strongly stained. RNA blot analysis confirmed the presence of specific mRNA transcript in the gastrointestinal mucosa, and in situ hybridization revealed that HAI-1 mRNA showed a similar cellular distribution pattern. Although HAI-1 was not expressed in normal hepatocytes, strong immunoreactivity was observed on the epithelium of pseudo-bile ducts and on the surface of scattered hepatocytes in fulminant hepatitis. The enhanced expression was also noted in regenerating tubule epithelial cells of the kidney after infarction. We conclude that HAI-1 is preferentially expressed in the simple columnar epithelium of the mucosal surface and duct, that the predominant localization of HAI-1 is the cell surface, and that the expression of HAI-1 can be modulated by tissue injury and regeneration.

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“…HGF is biosynthesized and secreted as single-chain HGF (scHGF), and proteolytic cleavage between R494 and V495 results in its conversion to two-chain HGF (tcHGF) (HGF refers to tcHGF unless otherwise noted) [12,13]. Both scHGF and tcHGF bind to Met, but only tcHGF activates it, which has been puzzling regarding the structural basis for Met's activation by HGF [36][37][38]. After the cleavage of scHGF, the newly formed N-terminal region of the β-subunit is inserted into a cavity in the SP domain that allosterically changes the conformation of the SP domain and enables the SP domain to bind to Met and tcHGF to activate Met [39][40][41].…”

Section: Discussionmentioning

confidence: 99%

Dimer Interface in Natural Variant NK1 Is Dispensable for HGF-Dependent Met Receptor Activation

Tahira

Sakai

Sato

et al. 2021

IJMS

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NK1, a splicing variant of hepatocyte growth factor (HGF), binds to and activates Met receptor by forming an NK1 dimer and 2:2 complex with Met. Although the structural mechanism underlying Met activation by HGF remains incompletely resolved, it has been proposed that the NK1 dimer structure participates in this activation. We investigated the NK1 dimer interface’s role in Met activation by HGF. Because N127, V140, and K144 are closely involved in the head-to-tail NK1 dimer formation, mutant NK1 proteins with replacement of these residues by alanine were prepared. In Met tyrosine phosphorylation assays, N127-NK1, V140-NK1, and K144-NK1 showed 8.3%, 23.8%, and 52.2% activity, respectively, compared with wild-type NK1. Although wild-type NK1 promoted cell migration and scattering, N127-NK1, V140-NK1, and K144-NK1 hardly or marginally promoted them, indicating loss of activity of these mutant NK1 proteins to activate Met. In contrast, mutant HGFs (N127-HGF, V140-HGF, and K144-HGF) with the same amino acid replacements as in NK1 induced Met tyrosine phosphorylation and biological responses at levels comparable to those of wild-type HGF. These results indicate that the structural basis responsible for NK1-dependent Met dimer formation and activation differs from, or is at least distinguishable from, the structural basis responsible for HGF-dependent Met activation.

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Activation of hepatocyte growth factor by proteolytic conversion of a single chain form to a heterodimer.

Cited by 178 publications

References 28 publications

The Sema domain of Met is necessary for receptor dimerization and activation

The Sema domain of Met is necessary for receptor dimerization and activation

Distribution of Hepatocyte Growth Factor Activator Inhibitor Type 1 (HAI-1) in Human Tissues: Cellular Surface Localization of HAI-1 in Simple Columnar Epithelium and Its Modulated Expression in Injured and Regenerative Tissues

Dimer Interface in Natural Variant NK1 Is Dispensable for HGF-Dependent Met Receptor Activation

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