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J Biol Chem. 2012 Apr 13;287(16):13371-81. doi: 10.1074/jbc.M111.318568. Epub 2012 Feb 21.

Identification of mannose receptor as receptor for hepatocyte growth factor β-chain: novel ligand-receptor pathway for enhancing macrophage phagocytosis.

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Kringle Pharma Joint Research Division for Regenerative Drug Discovery, Center for Advanced Science and Innovation, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan.


Hepatocyte growth factor (HGF), a heterodimer composed of the α-chain and β-chain, exerts multifunctional actions for tissue repair and homeostasis via its receptor, MET. HGF is cleaved by proteases secreted from inflammatory cells, and NK4 and β-chain remnant (HGF-β) are generated. Here, we provide evidence that HGF-β binds to a new receptor other than MET for promoting a host cell clearance system. By an affinity cross-linking, radiolabeled HGF-β was bound to liver non-parenchymal cells, particularly to Kupffer cells and sinusoidal endothelial cells, but not to parenchymal hepatocytes. The cross-linked complex was immunoprecipitated by anti-HGF antibody, but not anti-MET antibody, implying that HGF-β binds to non-parenchymal cells at a site distinct from MET. Mass spectrometric detection of the ligand receptor complex revealed that the binding site of HGF-β was the mannose receptor (MR). Actually, an ectopic expression of MR in COS-7 cells, which express no endogenous MR or MET, enabled HGF-β to bind these cells at a K(D) of 89 nM, demonstrating that MR is the new receptor for HGF-β. Interaction of HGF-β and MR was diminished by EGTA, and by an enzymatic digestion of HGF-β sugar chains, suggesting that MR may recognize the glycosylation site(s) of HGF-β in a Ca(2+)-dependent fashion. Notably, HGF-β, but not other MR ligands, enhanced the ingestion of latex beads, or of apoptotic neutrophils, by Kupffer cells, possibly via an F-actin-dependent pathway. Thus, the HGF-β·MR complex may provide a new pathway for the enhancement of cell clearance systems, which is associated with resolution of inflammation.

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