Vascular Origin of a Soluble Truncated Form of the Hepatocyte Growth Factor Receptor (c-met)

Wajih, Nadeem; Walter, Jennifer; Sane, David C.

doi:10.1161/hh0102.102756

Cited by 40 publications

(59 citation statements)

References 47 publications

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“…5 Genetic counts calculated on the basis of total number of risk alleles from five SNPs carried by each person: high-risk status (4-10 risky alleles) vs. low risk status (<4 risky alleles). 6 Genetic counts calculated on the basis of total number of risk alleles from six SNPs carried by each person: high-risk status (8-12 risky alleles) vs. low-risk status (<8 risky alleles). 7 Genetic counts calculated on the basis of total number of risk alleles from eleven SNPs carried by each person: high-risk status (11-22 risky alleles) vs. low-risk status (<11 risky alleles).…”

Section: Discussionmentioning

confidence: 99%

“…6 In the mature c-Met protein with a disulfide-linked heterodimer a (50 kDa) and b (145 kDa) chain, 7 the b chain spans both the extracellular membrane domain to which HGF binds and the cytoplasmic domain, which favors tyrosine kinase actions. 8,9 Through a proteolysis process, an integral c-Met protein can be released from the endothelial cell membrane, facilitating the generation of soluble truncated c-Met protein.…”

mentioning

confidence: 99%

“…This soluble truncated form of c-Met, consisting of the entire extracellular portion of the membrane domain, competitively binds to HGF instead of the integral c-Met with reduced affinity. 6 Alternative binding to soluble truncated c-Met indicates the possibility of the creation of opposite cellular signaling to interrupt tumorgenesis.…”

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confidence: 99%

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Soluble c‐Met protein as a susceptible biomarker for gastric cancer risk: A nested case‐control study within the Korean Multicenter Cancer Cohort

Yang¹,

Yang²,

Kim³

et al. 2012

Intl Journal of Cancer

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This study was conducted to evaluate the relevance of the soluble form of c-Met protein, a truncated form of the c-Met membrane receptor involved in the CagA pathway, as a potential biomarker for gastric cancer. Among 290 gastric cancer case-control sets selected from the Korean Multicenter Cancer Cohort, the plasma concentrations of soluble c-Met protein were measured with enzyme-linked immunosorbent assays. Using analysis of variance and covariance models with age, sex, smoking, Helicobacter pylori infection, and CagA seropositivity, the mean concentrations of soluble c-Met protein between cases and controls were compared. To evaluate the association between gastric cancer and a c-Met protein level, odds ratios and 95% confidence intervals were estimated using conditional logistic regression models. Interactions between CagA-related genes and the soluble c-Met protein concentration were also investigated. The overall median plasma concentration of soluble c-Met among cases was significantly lower than those of controls (1.390 vs. 1.610 ng/mL, p < 0.0001). Closer to the onset of gastric cancer, the soluble c-Met protein level decreased linearly in a time-dependent manner (p for trend 5 0.0002). The combined effects between the CagA-related genes and the soluble c-Met protein concentration significantly intensified risks for gastric cancer. Restricted analyses including cases that had been diagnosed within 1 year after entering the cohort had a fair degree of ability (area under the receiver operating characteristic curve of 0.73-0.77) to discriminate gastric cancer cases from normal controls. Our findings demonstrate the potential of the soluble form of c-Met protein as a novel biomarker for gastric cancer. The beneficial effects of a high soluble c-Met concentration in human plasma are strongly supported.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Soluble c‐Met protein as a susceptible biomarker for gastric cancer risk: A nested case‐control study within the Korean Multicenter Cancer Cohort

Yang¹,

Yang²,

Kim³

et al. 2012

Intl Journal of Cancer

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“…Unlike CBL-mediated endosomal degradation, regulated proteolysis of MET is ligand-and ubiquitin-independent and does not require the kinase activity of the receptor: the mechanism occurs basally and affords MET signalling with chronic, low-grade attenuation under steady-state conditions. The shedding of MET that is catalysed by ADAM metalloproteases can be acutely enhanced by various agents such as phorbol esters, suramin, lysophosphatidic acid and monoclonal antibodies (mAbs) against the MET ectodomain 94,95,96,97,98,99,100,101,102 . Importantly, the extracellular shedding of MET not only decreases the number of receptor molecules on the cell surface but also generates a decoy moiety that interacts with both HGF (by sequestering the ligand) and full-length MET (by impairing dimerization and transactivation of the native receptor) to further inhibit MET signalling 103,104 .…”

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

1,083

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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“…Many other fragments of Met have been described, but their biological functions, and the mechanisms involved in their generation have not been investigated. Examples include an extracellular fragment of Met, released upon ectodomain shedding into the culture supernatant (Prat et al, 1991;Galvani et al, 1995;Wajih et al, 2002), and a labile 55-kDa intracellular fragment of Met produced in epithelial cells (Jeffers et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

Down-Regulation of the Met Receptor Tyrosine Kinase by Presenilin-dependent Regulated Intramembrane Proteolysis

Foveau

Ancot

Leroy

et al. 2009

MBoC

100

113

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Vascular Origin of a Soluble Truncated Form of the Hepatocyte Growth Factor Receptor (c-met)

Cited by 40 publications

References 47 publications

Soluble c‐Met protein as a susceptible biomarker for gastric cancer risk: A nested case‐control study within the Korean Multicenter Cancer Cohort

Soluble c‐Met protein as a susceptible biomarker for gastric cancer risk: A nested case‐control study within the Korean Multicenter Cancer Cohort

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

Down-Regulation of the Met Receptor Tyrosine Kinase by Presenilin-dependent Regulated Intramembrane Proteolysis

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