Down-regulation of MET, the receptor for hepatocyte growth factor

Hammond, Dean E.; Urbé, Sylvie; Woude, George F. Vande; Clague, Michael J.

doi:10.1038/sj.onc.1204475

Cited by 160 publications

(159 citation statements)

References 39 publications

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“…We also wished to assess whether PRS-110-induced internalization differed from the classical ligand-induced internalization. It is known that upon HGF stimulation MET is endocytosed in clathrin-coated vesicles and directed to early endosome compartments so this was examined (46). As anticipated, our data shows that HGF leads to colocalization of the receptor with early endosomal vesicles (EEA-1 positive).…”

Section: Discussionsupporting

confidence: 58%

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: Discussionsupporting

confidence: 58%

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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“…Ligand-dependent endocytosis of RTKs was the common mechanism of receptor inactivation and recycling [30][31][32][33][34][35]44,45]. Consistent to the study in HeLa cells [35], the binding of HGF to c-Met triggers internalization and redistribution of c-Met to the perinulear compartment in HBEpCs.…”

Section: Discussionmentioning

confidence: 65%

“…It is well established that many transmembrane receptors, such as EGF-R and c-Met, become internalized upon ligand stimulation [30][31][32][33]. It has been reported that upon HGF stimulation, c-Met is rapidly internalized via clathrin-coated vesicles and traffics through an early endosomal compartment, which is independent of the proteasome-mediated degradative pathway [34].…”

Section: Introductionmentioning

confidence: 99%

Lysophosphatidic acid modulates c-Met redistribution and hepatocyte growth factor/c-Met signaling in human bronchial epithelial cells through PKC δ and E-cadherin

Zhao¹,

He²,

Stern³

et al. 2007

Cellular Signalling

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Previously we demonstrated that ligation of lysophosphatidic acid (LPA) to G protein-coupled LPA receptors induces transactivation of receptor tyrosine kinases (RTKs), such as platelet-derived growth factor receptor beta (PDGF-Rβ) and epidermal growth factor receptor (EGF-R), in primary cultures of human bronchial epithelial cells (HBEpCs). Here we examined the role of LPA on c-Met redistribution and modulation of hepatocyte growth factor ( These results demonstrate that LPA regulates c-Met function through PKC δ-and E-cadherin in HBEpCs, suggesting an alternate function of the cross-talk between G-protein coupled receptors (GPCRs) and RTKs in HBEpCs.

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“…This terminates signalling by sequestering MET from the cytosol and preventing it being recycled by the plasma membrane. Finally, the multivesicular bodies fuse with the lysosomes and MET undergoes proteolytic demolition 88,89 . Seemingly active MET is not polyubiquitylated, and is therefore unlikely to be targeted for degradation by theproteasome 87 ; however, proteasomal destruction of MET can occur in an ubiquitin-independent manner (see below).…”

Section: Regulation Of Met Signallingmentioning

confidence: 99%

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

Trusolino

Bertotti

Comoglio

2010

Nat Rev Mol Cell Biol

1,081

1,076

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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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Down-regulation of MET, the receptor for hepatocyte growth factor

Cited by 160 publications

References 39 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

Lysophosphatidic acid modulates c-Met redistribution and hepatocyte growth factor/c-Met signaling in human bronchial epithelial cells through PKC δ and E-cadherin

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

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