Suramin modulates cellular levels of hepatocyte growth factor receptor by inducing shedding of a soluble form

Galvani, Arturo; Cristiani, Cinzia; Carpinelli, Patrizia; Landonio, Antonella; Bertolero, Federico

doi:10.1016/0006-2952(95)00219-p

Cited by 40 publications

(31 citation statements)

References 26 publications

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“…The MET protein contains a disulfide link between the ␣-(50 kDa) and ␤-subunits (145 kDa), forming a ␣/␤-heterodimer (31)(32)(33). Notably, soluble MET (sMET) is generated via ectodomain shedding, in which the ␤-subunit is proteolytically cleaved and released (34). We confirmed that the molecular weight of the MET isoform detected in our PE sample was equivalent to sMET (90 kDa; Fig.…”

Section: Fig 3 Strategy Used To Select Malignancy-related Pe Biomarsupporting

confidence: 79%

In-depth Proteomic Analysis of Six Types of Exudative Pleural Effusions for Nonsmall Cell Lung Cancer Biomarker Discovery

Liu

Chen

Wang³

et al. 2015

Molecular & Cellular Proteomics

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Pleural effusion (PE), a tumor-proximal body fluid, may be a promising source for biomarker discovery in human cancers. Because a variety of pathological conditions can lead to PE, characterization of the relative PE proteomic profiles from different types of PEs would accelerate discovery of potential PE biomarkers specifically used to diagnose pulmonary disorders. Using quantitative proteomic approaches, we identified 772 nonredundant proteins from six types of exudative PEs, including three malignant PEs (MPE, from lung, breast, and gastric cancers), one lung cancer paramalignant PE, and two benign diseases (tuberculosis and pneumonia). Spectral counting was utilized to semiquantify PE protein levels. Principal component analysis, hierarchical clustering, and Gene Ontology of cellular process analyses revealed differential levels and functional profiling of proteins in each type of PE. We identified 30 candidate proteins with twofold higher levels (q<0.05) in lung cancer MPEs than in the two benign PEs. Three potential markers, MET, DPP4, and PTPRF, were further verified by ELISA using 345 PE samples. The protein levels of these potential biomarkers were significantly higher in lung cancer MPE than in benign diseases or lung cancer paramalignant PE. The area under the receiver-operator characteristic curve for three combined biomarkers in discriminating lung cancer MPE from benign diseases was 0.903. We also observed that the PE protein levels were more clearly discriminated in effusions in which the cytological examination was positive and that they would be useful in rescuing the false negative of cytological examination in diagnosis of nonsmall cell lung cancer-MPE. Western blotting analysis further demonstrated that MET overexpression in lung cancer cells would contribute to the elevation of soluble MET in MPE. Our results collectively demonstrate the utility of label-free quantitative proteomic approaches in establishing differential PE proteomes and provide a new database of proteins that can be used to facilitate identification of pulmonary disorder-related biomarkers. Molecular & Cellular Proteomics

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Section: Fig 3 Strategy Used To Select Malignancy-related Pe Biomarsupporting

confidence: 79%

In-depth Proteomic Analysis of Six Types of Exudative Pleural Effusions for Nonsmall Cell Lung Cancer Biomarker Discovery

Liu

Chen

Wang³

et al. 2015

Molecular & Cellular Proteomics

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“…Met ectodomain shedding has been described previously on the basis of initial observations of a soluble extracellular form of Met (Prat et al, 1991;Crepaldi et al, 1994). This process has been observed in various cell types and has been induced with different agents such as PMA, suramine, epidermal growth factor (EGF), lysophosphatidic acid (LPA), and HGF/SF (Prat et al, 1991;Galvani et al, 1995;Nath et al, 2001;Wajih et al, 2002). In addition, other fragments have been observed, such as phosphorylated membrane-anchored fragments degraded via the proteosomal pathway or labile nuclear fragments (Jeffers et al, 1997;Pozner-Moulis et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

“…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

112

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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

1,026

1,038

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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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Suramin modulates cellular levels of hepatocyte growth factor receptor by inducing shedding of a soluble form

Cited by 40 publications

References 26 publications

In-depth Proteomic Analysis of Six Types of Exudative Pleural Effusions for Nonsmall Cell Lung Cancer Biomarker Discovery

In-depth Proteomic Analysis of Six Types of Exudative Pleural Effusions for Nonsmall Cell Lung Cancer Biomarker Discovery

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

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

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