MET signalling: 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: 37.16). 12/2010; 11(12):834-48. DOI: 10.1038/nrm3012
Source: PubMed

ABSTRACT 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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    ABSTRACT: Hepatocyte growth factor (HGF) and its receptor, Met, regulate skeletal muscle differentiation. In the present study, we identified a novel alternatively spliced isoform of Met lacking exon 13 (designated Δ13Met), which is expressed mainly in human skeletal muscle. Alternative splicing yielded a truncated Met having extracellular domain only, suggesting an inhibitory role. Indeed, Δ13Met expression led to a decrease in HGF-induced tyrosine phosphorylation of Met and ERK phosphorylation as well as cell proliferation and migration via sequestration of HGF. Interestingly, in human primary myoblasts undergoing differentiation, Δ13Met mRNA and protein levels were rapidly increased, concomitantly with a decrease in wild-type Met mRNA and protein. Inhibition of D13Met with siRNA led to a decreased differentiation whereas its overexpression potentiated differentiation of human primary myoblasts. Furthermore, in notexin-induced mouse injury model, exogenous D13Met expression enhanced regeneration of skeletal muscle, further confirming a stimulatory role of the isoform in muscle cell differentiation. In summary, we identified a novel alternatively spliced inhibitory isoform of Met that stimulates muscle cell differentiation, which confers a new means to control muscle differentiation and/or regeneration. Copyright © 2014, The American Society for Biochemistry and Molecular Biology.
    The Journal of biological chemistry. 12/2014;
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    ABSTRACT: MET receptor tyrosine kinase and its natural ligand, hepatocyte growth factor, have been implicated in a variety of cancers, including non-small cell lung cancer (NSCLC). Mechanisms by which cellular deregulation of MET occurs include overexpression, genomic amplification, mutation, or alternative splicing. MET overexpression or activation is a known cause of acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in NSCLC. Inhibition of MET signaling in these EGFR tyrosine kinase inhibitor-resistant cells may potentially restore sensitivity to EGFR inhibitors. Tivantinib (ARQ 197), reported as a small-molecule MET inhibitor, has demonstrated antitumor activity in early clinical studies. This review focuses on MET and lung cancer, the clinical development of tivantinib, the clinical trials of tivantinib in NSCLC to date, its current/emerging role in the management of NSCLC, and future directions.
    Cancer Management and Research 01/2014; 6:397-404.
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    ABSTRACT: Ischaemic heart disease is the main cause of death in western countries. Cardiac tissue is primarily damaged by cardiomyocyte cell death triggered by low oxygen supply to the heart (hypoxia). The current therapeutic approach is coronary angioplastic intervention or thrombolytic treatments to resume blood flow in the ischaemic heart. Unfortunately, reperfusion itself causes a burst of ROS production responsible for cardiomyocyte death and myocardial dysfunction. Indeed, the majority of patients surviving to acute myocardial infarction undergoes progressive heart failure, with 50% mortality at five years from diagnosis. Apoptosis of cardiomyocytes is dangerous both during ischaemia and reperfusion. In line with this concept, we have shown that treatment of H9c2 cardiomyoblasts with cobalt chloride (CoCl2), a chemical mimetic of hypoxia, induces caspase-dependent apoptosis. Unexpectedly, we found that 3-methyladenine, an inhibitor of autophagy initiation, partially prevents CoCl2-mediated cell death, indicating that also autophagy contributes to cardiomyoblast death. Consistently, we found an increase in the autophagic flux in dying cells. Mechanistically, we have shown that CoCl2 upregulates Redd1, Bnip3 and phospho-AMPK proteins and causes inhibition of mTOR, the main negative regulator of autophagy. In light of these observations, it is important to discover new therapeutic tools displaying a dual prosurvival mechanism. To this aim, we have analyzed the cardioprotective action of HGF/Met axis in hypoxic injury. To activate Met signaling we have used either the HGF ligand or two different monoclonal antibodies (mAbs) directed against the extracellular moiety of Met receptor. Owing a divalent structure, the two mAbs can dimerize and activate Met receptor, thus displaying agonist activity. Hypoxic injury was fully prevented by either HGF or Met agonist mAbs through both anti-apoptotic and anti-autophagic functions. By pharmacological inhibition we showed that activation of mTOR is the protective signaling downstream to Met, being involved in the anti-autophagic effect. In conclusion, HGF or Met agonist mAbs promote cell survival by negative dual regulation of apoptotic and autophagic cell death and represent promising new therapeutic tools to manage cardiac diseases.
    Receptors & Clinical Investigation. 09/2014; 1:292-294.

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