Mast Cell and Neutrophil Peptidases Attack an Inactivation Segment in Hepatocyte Growth Factor to Generate NK4-like Antagonists

Raymond, Wilfred W.; Cruz, Anthony; Caughey, George H.

doi:10.1074/jbc.m511154200

Cited by 33 publications

(34 citation statements)

References 40 publications

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“…This apparent contradiction may be explained by, for example, the cellular location of the receptor; initial intracellular cmet may be transported to the plasma membrane at the onset of EAE where it would then be available for activation by HGF. Alternatively, natural occurring c-met antagonist such as NK1 and 2 and NK4-like protein (Chan et al 1991;Raymond et al 2006), both splice variants of full length HGF, may inhibit c-met activation in the CNS under systemic conditions. CNS injury may down regulate the levels of these antagonists, allowing c-met activation without a preceding increase in HGF.…”

Section: Hgf and C-met Expression In Eaementioning

confidence: 99%

Expression of the HGF receptor c‐met by macrophages in experimental autoimmune encephalomyelitis

Moransard

Sawitzky

Fontana

et al. 2009

Glia

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Hepatocyte growth factor (HGF) is a pleiotropic cytokine able to evoke a wide array of cellular responses including proliferation, migration, and survival through activation of its receptor c‐met. Various types of leukocytes have been described to express c‐met suggesting that HGF/c‐met signaling may directly influence leukocyte responses in inflammation. We have investigated the HGF/c‐met pathway in experimental autoimmune encephalomyelitis (EAE), a common mouse model of multiple sclerosis (MS), in which macrophages play a dual role, contributing directly to CNS damage at disease onset but promoting recovery during remission by removing myelin debris. Here we show that during EAE both HGF and c‐met are expressed in the CNS and that c‐met is activated. We subsequently demonstrate that c‐met is primarily expressed in inflammatory lesions by macrophages and a small number of dendritic cells (DCs) and oligodendrocyte progenitor cells (OPCs) but not by microglia or T cells. Complementary in vitro experiments show that only LPS and TNFα, but not IL‐6, IL‐10, or IL‐13, are able to induce c‐met expression in macrophages. In addition, using TNF signaling deficient macrophages we demonstrate that LPS and TNFα induce c‐met through distinct pathways. Furthermore, TNFα‐ and LPS‐induced c‐met is functional because treatment of macrophages with recombinant HGF results in rapid phosphorylation of c‐met. Interestingly, HGF/c‐met signaling does not modulate cytokine expression, phagocytosis, or antigen presentation but promotes proliferation of activated macrophages. Taken together, our data indicate a pro‐inflammatory role for the HGF/c‐met pathway in EAE rather than a role in the initiation of repair mechanisms. © 2009 Wiley‐Liss, Inc.

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Section: Hgf and C-met Expression In Eaementioning

confidence: 99%

Expression of the HGF receptor c‐met by macrophages in experimental autoimmune encephalomyelitis

Moransard

Sawitzky

Fontana

et al. 2009

Glia

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“…The α-chain of HGF also binds to the Met sema domain independently of the β-chain (10). Cleavage of HGF before cysteine 487 occurs with mast cell chymase, plasma kallikrein, or neutrophil elastase, each of which generates a free α-chain that can function as a competitive inhibitor of HGF (2,11). A synthetic version of the HGF α-chain containing the N-terminal domain and four kringle domains (NK4) has been explored as a HGF antagonist for anticancer therapy (12)(13)(14)(15).…”

mentioning

confidence: 99%

Structural basis for agonism and antagonism of hepatocyte growth factor

Tolbert¹,

Daugherty-Holtrop²,

Gherardi

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Hepatocyte growth factor (HGF) is an activating ligand of the Met receptor tyrosine kinase, whose activity is essential for normal tissue development and organ regeneration but abnormal activation of Met has been implicated in growth, invasion, and metastasis of many types of solid tumors. HGF has two natural splice variants, NK1 and NK2, which contain the N-terminal domain (N) and the first kringle (K1) or the first two kringle domains of HGF. NK1, which is a Met agonist, forms a head-to-tail dimer complex in crystal structures and mutations in the NK1 dimer interface convert NK1 to a Met antagonist. In contrast, NK2 is a Met antagonist, capable of inhibiting HGF's activity in cell proliferation without clear mechanism. Here we report the crystal structure of NK2, which forms a "closed" monomeric conformation through interdomain interactions between the N-domain and the second kringle domain (K2). Mutations that were designed to open up the NK2 closed conformation by disrupting the N/K2 interface convert NK2 from a Met antagonist to an agonist. Remarkably, this mutated NK2 agonist can be converted back to an antagonist by a mutation that disrupts the NK1/NK1 dimer interface. These results reveal the molecular determinants that regulate the agonist/antagonist properties of HGF NK2 and provide critical insights into the dimerization mechanism that regulates the Met receptor activation by HGF.cancer metastasis | crystal structure | HGF agonist | HGF antagonist | Met receptor tyrosine kinase H epatocyte growth factor (HGF) and the Met tyrosine kinase receptor form a unique ligand-receptor signaling system where HGF is the only known endogenous ligand that activates Met. HGF is also known as a scattering factor, and its signaling through Met activation is involved in promoting cell proliferation, survival, migration, and branching in a variety of cell types with important roles in angiogenesis, wound repair, and cell migration during development (1, 2). Inappropriate expression of Met or HGF has been implicated in many cancers and is associated with an aggressive phenotype and poor prognosis (1, 3) (www.vai.org/met). Thus, inhibition of Met activity, either by small molecule kinase inhibitors or by protein-based HGF antagonists, has become an important and rational strategy for developing anticancer therapeutics.The Met extracellular domain (ECD), which encompasses approximately 900 amino acids (25-932), is cleaved into α and β chains by the furin protease between residues 307 and 308. The first 519 amino acids of Met form a 7-bladed β-propeller domain, called sema domain, with homology to the semaphorin and plexin protein families (4, 5). Following the sema domain are a cysteine-rich domain and four immunoglobulin-like domains. The sema domain of Met is necessary and sufficient for binding and activation of the receptor by HGF (6). It is believed that HGF induced Met activation is mediated through a formation of a 2∶2 complex where Met dimerization is primarily mediated by dimer formation of HGF (7,8).HGF is a disu...

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“…Under inflammation, HGF is digested by leukocyte-derived proteases, such as elastase, leading to generations of NK4 and HGF-␤ (i.e. HGF-daughter molecules) (13,17). We identified perlecan as a new receptor of NK4: the NK4⅐perlecan complex inhibits assembly of fibronectin, a key integrin ligand for supporting endothelial cell growth, resulting in the arrest of tumor angiogenesis (16).…”

Section: Discussionmentioning

confidence: 99%

“…We recently reported that NK4 interacts with perlecan, resulting in the inhibition of surface fibronectin assembly and integrin-dependent endothelial growth (16). In addition to pancreatic elastase (11,13), leukocyte proteases and skin kallikrein also cleave HGF and generates an NK4-like fragment (17,18). In contrast to the unique functions of NK4, it is still unknown whether another HGF fragment, HGF-␤, has a biological function(s).…”

mentioning

confidence: 98%

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Identification of Mannose Receptor as Receptor for Hepatocyte Growth Factor β-Chain

Ohnishi

Oka

Mizuno

et al. 2012

Journal of Biological Chemistry

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Mast Cell and Neutrophil Peptidases Attack an Inactivation Segment in Hepatocyte Growth Factor to Generate NK4-like Antagonists

Cited by 33 publications

References 40 publications

Expression of the HGF receptor c‐met by macrophages in experimental autoimmune encephalomyelitis

Expression of the HGF receptor c‐met by macrophages in experimental autoimmune encephalomyelitis

Structural basis for agonism and antagonism of hepatocyte growth factor

Identification of Mannose Receptor as Receptor for Hepatocyte Growth Factor β-Chain

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