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: 36.46). 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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Available from: Livio Trusolino, Dec 30, 2013
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    • "As the clinical HDI course is pursued, it is becoming important to identify the potential mechanisms of resistance to increase efficacy and identify potential drug combinations. MET, a transmembrane tyrosine kinase receptor for hepatocyte growth factor (HGF), plays an important role in the development of both human cancer and drug resistance in cancer cells [10] [11] [12]. "
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    ABSTRACT: Although SAHA is approved for the treatment of cutaneous T-cell lymphoma by the U.S. Food and Drug Administration, clinical trials using SAHA as a monotherapy or in combination with other chemotherapeutic agents in solid tumors have not met with success, and the mechanisms of tolerance remain unknown. In this study, using the prostate cancer cell line PC3 and the non-small lung cancer cell line A549, which have limited sensitivity to SAHA, we found that SAHA triggered MET and AKT phosphorylation at clinical concentrations. siRNA silencing of MET enhanced SAHA induced apoptosis in PC3 and A549 cells. However, MET protein expression and HGF secretion were not affected by SAHA, suggesting that the SAHA-induced MET activation was not due to MET over-expression or HGF paracrine secretion. However, mRNA and protein expression of the laminin receptor integrin α5β1 was up-regulated by SAHA prior to MET activation. Silencing of integrin α5β1 abolished SAHA-triggered MET phosphorylation, suggesting the involvement of integrin α5β1 in MET activation. Further, the combination of SAHA and XL184 resulted in a synergistic induction of cancer cell apoptosis and a synergistic inhibition of tumor growth. These data indicate that SAHA triggered MET activation in an HGF independent manner. This effect is partially involved in the resistance to SAHA in solid cancers, warranting further clinical investigation into combining SAHA with MET inhibitors in solid cancer treatment. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.
    Cancer Letters 11/2014; 356(2). DOI:10.1016/j.canlet.2014.10.034 · 5.62 Impact Factor
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    • "kB target gene ) ( Harrison and Farzaneh , 2000 ) . This was excluded , at least in epithelial cell lines , by lack of HGF mRNA or protein expres - sion after TNF - a treatment . ( ii ) Second , as it was shown that MET can be activated by physical interaction with other sur - face receptors , including molecules lacking tyrosine kinase activity ( Trusolino et al . , 2010 ) , we hypothesized that the acti - vated TNF receptor could oligomerize with MET . This was ruled out by lack of receptor co - precipitation , and by lack of receptor co - localization after fluorescent immunostaining and confocal microscopy . We can also hypothesize that MET phosphorylation is mediated by an intracellular kinase . A l"
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    ABSTRACT: The inflammatory cytokine Tumor Necrosis Factor Alpha (TNF-α) is known to trigger invasive growth, a physiological property for tissue healing, turning into a hallmark of progression in cancer. However, the invasive response to TNF-α relies on poorly understood molecular mechanisms. We thus investigated whether it involves the MET oncogene, which regulates the invasive growth program by encoding the tyrosine kinase receptor for Hepatocyte Growth Factor (HGF). Here we show that the TNF-α pro-invasive activity requires MET function, as it is fully inhibited by MET-specific inhibitors (small-molecules, antibodies, and siRNAs). Mechanistically, we show that TNF-α induces MET transcription via NF-κB, and exploits MET to sustain MEK/ERK activation and Snail accumulation, leading to E-cadherin downregulation. We then show that TNF-α not only induces MET expression in cancer cells, but also HGF secretion by fibroblasts. Consistently, we found that, in human colorectal cancer tissues, high levels of TNF-α correlates with increased expression of both MET and HGF. These findings suggest that TNF-α fosters a HGF/MET pro-invasive paracrine loop in tumors. Targeting this ligand/receptor pair would contribute to prevent cancer progression associated with inflammation.
    Molecular Oncology 09/2014; DOI:10.1016/j.molonc.2014.09.002 · 5.94 Impact Factor
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    • "After satellite cell activation, expression of muscle regulatory factors, Myf5 and MyoD occurs, and at the beginning of differentiation, myogenin and MRF4 are expressed [8]. When HGF binds to the c-Met receptor tyrosine kinase, its cytoplasmic Tyr residues are autophosphorylated and bind the scaffolding adaptor protein Gab1, which leads to the activation of phosphatidylinositol 3-kinase (PI3K) and Ras-ERK mitogen-activated protein kinase cascade (Fig. 1) [9]. This suggests that controlled activation of c-Met signaling can be exploited in regenerative medicine. "
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    ABSTRACT: Muscular dystrophies comprise a large group of inherited disorders that lead to progressive muscle wasting. We wanted to investigate if targeting satellite cells can enhance muscle regeneration and thus increase muscle mass. We treated mice with hepatocyte growth factor and leukemia inhibitory factor under three conditions: normoxia, hypoxia and during myostatin deficiency. We found that hepatocyte growth factor treatment led to activation of the Akt/mTOR/p70S6K protein synthesis pathway, up-regulation of the myognic transcription factors MyoD and myogenin, and subsequently the negative growth control factor, myostatin and atrophy markers MAFbx and MuRF1. Hypoxia-induced atrophy was partially restored by hepatocyte growth factor combined with leukemia inhibitory factor treatment. Dividing satellite cells were three-fold increased in the treatment group compared to control. Finally, we demonstrated that myostatin regulates satellite cell activation and myogenesis in vivo following treatment, consistent with previous findings in vitro. Our results suggest, not only a novel in vivo pharmacological treatment directed specifically at activating the satellite cells, but also a myostatin dependent mechanism that may contribute to the progressive muscle wasting seen in severely affected patients with muscular dystrophy and significant on-going regeneration. This treatment could potentially be applied to many conditions that feature muscle wasting to increase muscle bulk and strength.
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