Crystal structure of the HGF β-chain in complex with the Sema domain of the Met receptor

Stamos, Jennifer L.; Lazarus, Robert A.; Yao, Xiaoyi; Kirchhofer, Daniel; Wiesmann, Christian

doi:10.1038/sj.emboj.7600243

Cited by 219 publications

(295 citation statements)

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“…The resolved crystal structure of the ligand and receptor complex identified the interaction of MET Sema domain with the b chain of HGF (38). Multiple indirect lines of evidence support the interaction of IPT domain with the a chain of HGF (39). It is believed that these distinct binding sites cooperate to induce maximal receptor signaling.…”

Section: Discussionmentioning

confidence: 98%

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A Highly Potent and Specific MET Therapeutic Protein Antagonist with Both Ligand-Dependent and Ligand-Independent Activity

Olwill

Joffroy

Gille

et al. 2013

Molecular Cancer Therapeutics

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Activation of the MET oncogenic pathway has been implicated in the development of aggressive cancers that are difficult to treat with current chemotherapies. This has led to an increased interest in developing novel therapies that target the MET pathway. However, most existing drug modalities are confounded by their inability to specifically target and/or antagonize this pathway. Anticalins, a novel class of monovalent small biologics, are hypothesized to be "fit for purpose" for developing highly specific and potent antagonists of cancer pathways. Here, we describe a monovalent full MET antagonist, PRS-110, displaying efficacy in both ligand-dependent and ligand-independent cancer models. PRS-110 specifically binds to MET with high affinity and blocks hepatocyte growth factor (HGF) interaction. Phosphorylation assays show that PRS-110 efficiently inhibits HGF-mediated signaling of MET receptor and has no agonistic activity. Confocal microscopy shows that PRS-110 results in the trafficking of MET to late endosomal/lysosomal compartments in the absence of HGF. In vivo administration of PRS-110 resulted in significant, dose-dependent tumor growth inhibition in ligand-dependent (U87-MG) and ligand-independent (Caki-1) xenograft models. Analysis of MET protein levels on xenograft biopsy samples show a significant reduction in total MET following therapy with PRS-110 supporting its ligand-independent mechanism of action. Taken together, these data indicate that the MET inhibitor PRS-110 has potentially broad anticancer activity that warrants evaluation in patients. Mol Cancer Ther; 12(11); 2459-71. Ó2013 AACR.

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Section: Discussionmentioning

confidence: 98%

“…This is also the location of the furin cleavage site between the MET a and b chains. This loop is disordered in the crystal structure and is presumably highly flexible (38)(39)(40)(41)(42). In addition, PRS-110 binds to an extended b-hairpin of the IPT1 domain (WDFGFRRNNKFD).…”

Section: Epitope Mapping Of Prs-110mentioning

confidence: 99%

A Highly Potent and Specific MET Therapeutic Protein Antagonist with Both Ligand-Dependent and Ligand-Independent Activity

Olwill

Joffroy

Gille

et al. 2013

Molecular Cancer Therapeutics

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“…The high-affinity site is located in the α-chain and recognizes the IPT3 and IPT4 domains of MET independently of HGF processing and maturation 155 . The low-affinity site lies within the β-chain, is exposed only after HGF activation and interacts with the Sema domain of MET 156 . This latter association is depicted as a ribbon representation (see the figure, part c).…”

Section: Competing Interests Statementmentioning

confidence: 99%

MET signalling: principles and functions in development, organ regeneration and cancer

Trusolino

Bertotti

Comoglio

2010

Nat Rev Mol Cell Biol

1,061

1,106

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The MET tyrosine kinase receptor (also known as the HGF receptor) promotes tissue remodelling, which underlies developmental morphogenesis, wound repair, organ homeostasis and cancer metastasis, by integrating growth, survival and migration cues in response to environmental stimuli or cell-autonomous perturbations. The versatility of MET-mediated biological responses is sustained by qualitative and quantitative signal modulation. Qualitative mechanisms include the engagement of dedicated signal transducers and the subcellular compartmentalization of MET signalling pathways, whereas quantitative regulation involves MET partnering with adaptor amplifiers or being degraded through the shedding of its extracellular domain or through intracellular ubiquitylation. Controlled activation of MET signalling can be exploited in regenerative medicine, whereas MET inhibition might slow down tumour progression.Throughout embryogenesis, cells bud off from developing tissues and move outwards to shape and pattern the complex architecture of prospective organs 1 . A similar process occurs in adult life during wound healing and tissue repair, when lingering cells migrate into injury sites to recreate the pre-existing structures 2 . The acquisition of cell motility is necessary, but not sufficient, for this event. Cells that detach from their neighbours must elude anoikis, a form of apoptotic cell death that occurs when cells lose adhesion with the extracellular matrix 3 . Moreover, migratory cells undergo extensive mitotic divisions to produce 'founder populations', which settle in newly forming organs during development or colonize worn tissues during repair 4,5 . The normal phases of embryogenesis and organ regeneration strongly resemble the pathological process of tumour invasiveness: similarly to cells at the wound edge, cells at the tumour's leading front disrupt intercellular contacts and infiltrate the adjacent surroundings, where they resist anoikis and grow before lodging in the blood vessels for systemic dissemination 6 . This resemblance is not simply a biological correlate, it has a common mechanistic basis: cancer cells resurrect the latent schemes of cellular reorganization, which are usually confined to embryonic development and damaged adult organs, and leverage them to become competent for metastasization 7 . The activities -motility, survival and proliferation -that occur in developing, injured and neoplastic tissues embody a biological programme that is defined as 'invasive growth' 8 . This is triggered by extracellular stimuli that regulate the activity of several transcription factors that, in turn, modulate the expression of a number of proteins, ranging from cytoskeletal and cell-cell junctional components to cell cycle regulators and anti-apoptotic effectors 9, 10 . One major environmental inducer of invasive growth is hepatocyte growth factor (HGF, also known as scatter factor), the ligand for the MET tyrosine kinase receptor (also known as the HGF receptor) 11,12,13,14,15,16,17,18,19,20 (Box 1). ...

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“…By examining the MSP crystal structure data (PDB ID: 2ASU) (43), we note that R689 is located on the surface of the MSP β-chain and within a positively charged patch (L13 loop) that consists of a cluster of arginine residues including R683, which has been shown to be essential for MST1R binding (44) (Figure 3). The L13 loop borders the S1 specificity pocket (involving Y661, Q522 and Q568) and together, form the putative high-affinity binding surface for MST1R, resembling the structurally determined interaction between hepatocyte growth factor (scatter factor), which is structurally related to MSP, and its receptor, MET (45,46). Furthermore, the proximity of R689C to a conserved cysteine residue (C685) that establishes a critical disulfide bond with C657 may introduce aberrant bond formations and disrupt the structural integrity of the adjacent receptor binding surface.…”

Section: The Associated R689c Variant and Mst1 Functionmentioning

confidence: 99%

Gene-centric association mapping of chromosome 3p implicates MST1 in IBD pathogenesis

Goyette

Lefèbvre

et al. 2008

Mucosal Immunology

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Association mapping and candidate gene studies within IBD linkage regions, as well as genomewide association studies in CD have led to the discovery of multiple risk genes, but these only Corresponding author: John D. Rioux, Montreal Heart Institute, 5000 Belanger Street, Montreal, Quebec, Canada, H1T 1C8, rioux@inflammgen.org. HHS Public Access Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript explain a fraction of the genetic susceptibility observed in IBD. We have thus been pursuing a region on chromosome 3p21-22 showing linkage to CD and UC using a gene-centric association mapping approach. We identified twelve functional candidate genes by searching for literature cocitations with relevant keywords and for gene expression patterns consistent with immune/ intestinal function. We then performed an association study composed of a screening phase, where tagging SNPs were evaluated in 1020 IBD patients, and an independent replication phase in 745 IBD patients. These analyses identified and replicated significant association to IBD for four SNPs within a 1.2 Mb LD region. We then identified a non-synonymous coding variant (rs3197999, R689C) in the macrophage stimulating 1 (MST1) gene (p-value 3.62×10−6) that accounts for the association signal, and shows association to both CD and UC. MST1 encodes MSP, a protein regulating the innate immune responses to bacterial ligands. R689C is predicted to interfere with MSP binding to its receptor, suggesting a role for this gene in the pathogenesis of IBD.

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Crystal structure of the HGF β-chain in complex with the Sema domain of the Met receptor

Cited by 219 publications

References 42 publications

A Highly Potent and Specific MET Therapeutic Protein Antagonist with Both Ligand-Dependent and Ligand-Independent Activity

A Highly Potent and Specific MET Therapeutic Protein Antagonist with Both Ligand-Dependent and Ligand-Independent Activity

MET signalling: principles and functions in development, organ regeneration and cancer

Gene-centric association mapping of chromosome 3p implicates MST1 in IBD pathogenesis

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