MET signaling: Principles and functions in development, organ regeneration and cancer

Institute for Cancer Research and Treatment (IRCC), University of Torino Medical School, 10060 Candiolo, Torino, Italy.
Nature Reviews Molecular Cell Biology (Impact Factor: 37.81). 12/2010; 11(12):834-48. DOI: 10.1038/nrm3012
Source: PubMed


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.

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Available from: Livio Trusolino, Dec 30, 2013
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    • "They further showed that exosomemediated metastasis was dependent on expression of MET in exosomes, and that MET protein was increased in exosomes found in patients with advanced melanoma (Peinado et al., 2012). MET is an oncogenic receptor tyrosine kinase that promotes proliferation, motility, and migration, and is often aberrantly activated in tumors (Gherardi et al., 2012;Trusolino et al., 2010). These findings indicate that exosomal MET may be a potential therapeutic target or biomarker for metastatic disease. "
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    ABSTRACT: The Reproducibility Project: Cancer Biology seeks to address growing concerns about reproducibility in scientific research by conducting replications of selected experiments from a number of high-profile papers in the field of cancer biology. The papers, which were published between 2010 and 2012, were selected on the basis of citations and Altmetric scores (Errington et al., 2014). This Registered Report describes the proposed replication plan of key experiments from “Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET” by Peinado and colleagues, published in Nature Medicine in 2012 (Peinado et al., 2012). The key experiments being replicated are from Figures 4E, as well as Supplementary Figures 1C and 5A. In these experiments, Peinado and colleagues show tumor exosomes enhance metastasis to bones and lungs, which is diminished by reducing Met expression in exosomes (Peinado et al., 2012). The Reproducibility Project: Cancer Biology is a collaboration between the Center for Open Science and Science Exchange and the results of the replications will be published in eLife.
    Full-text · Article · Jan 2016 · eLife Sciences
    • "Many tumor-derived cytokines such as TGFb, IL-10, M-CSF and IL-6 are implicated in the development of tolerogenic DCs in tumors[169]. While aberrant MET signaling in tumors due to receptor amplification and ligand-independent receptor activation due to RTK synergy has been well documented[20,170,171], recent studies have shown that the tumor-associated stromal cells produce abundant quantities of HGF172173174. The possibility that deregulated HGF production within the tumor microenvironment may contribute to tumor growth via inducing the tolerogenic potential of tumor associated macrophages and DCs deserves to be investigated. "
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    ABSTRACT: Hepatocyte growth factor (HGF) signaling via the MET receptor is essential for embryonic development and tissue repair. On the other hand, deregulated MET signaling promotes tumor progression in diverse types of cancers. Even though oncogenic MET signaling remains the major research focus, the HGF–MET axis has also been implicated in diverse aspects of immune cell development and functions. In the presence of other hematopoietic growth factors, HGF promotes the development of erythroid, myeloid and lymphoid lineage cells and thrombocytes. In monocytes and macrophages responding to inflammatory stimuli, induction of autocrine HGF–MET signaling can contribute to tissue repair via stimulating anti-inflammatory cytokine production. HGF–MET signaling can also modulate adaptive immune response by facilitating the migration of Langerhans cells and dendritic cells to draining lymph nodes. However, MET signaling has also been shown to induce tolerogenic dendritic cells in mouse models of graft-versus-host disease and experimental autoimmune encephalomyelitis. HGF–MET axis is also implicated in promoting thymopoiesis and the survival and migration of B lymphocytes. Recent studies have shown that MET signaling induces cardiotropism in activated T lymphocytes. Further understanding of the HGF–MET axis in the immune system would allow its therapeutic manipulation to improve immune cell reconstitution, restore immune homeostasis and to treat immuno-inflammatory diseases.
    No preview · Article · Jan 2016 · Cytokine
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    • "The MET protein is a receptor tyrosine kinase (RTK) and the receptor for hepatocyte growth factor (HGF)/scatter factor (Boccaccio and Comoglio, 2006). Binding of HGF to MET initiates various biological responses including cell proliferation and survival, detachment from adjacent cells, epithelial to mesenchymal transition, degradation of and migration through extracellular matrices (Trusolino et al., 2010). While HGF/MET signalling is important for organogenesis and other physiological processes, aberrant activation of HGF/MET signalling facilitates metastasis in malignant tumors (Gherardi et al., 2012) and elevated expression of MET is associated with poor prognosis of glioma (Nabeshima et al., 1997; Kong et al., 2009; Liu et al., 2011; Miyamoto et al., 2011). "
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    ABSTRACT: Increased recycling and elevated cell-surface expression of receptors serve as a mechanism for persistent receptor-mediated signalling. We show that the neuron-enriched Na(+)/H(+) exchanger NHE5 is abundantly expressed in C6 glioma cells and plays an important part in regulating cell-surface expression of receptor tyrosine kinases MET and EGF receptor. NHE5 is associated with transferrin receptor- and Rab11-positive recycling endosomal membranes, and NHE5-knockdown by short hairpin RNA significantly elevates pH of transferrin receptor-positive recycling endosomes. We present evidence that NHE5 facilitates MET recycling to the plasma membrane, protects MET from degradation, modulates HGF-induced PI3K and MAPK signalling. Moreover, NHE5-depletion abrogates Rac1 and Cdc42 signalling, and actin cytoskeletal remodelling. We further show that NHE5-knockdown impairs directed cell migration and causes loss of cell polarity. Our study highlights a possible role of recycling endosomal pH in regulating receptor-mediated signaling through vesicular trafficking.
    Preview · Article · Dec 2015 · Molecular biology of the cell
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