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: 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.

  • Clinical Lung Cancer 02/2015; DOI:10.1016/j.cllc.2015.01.009 · 3.22 Impact Factor
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    ABSTRACT: Lung cancer is the leading cause of death for solid tumors worldwide with an annual mortality of over one million. Lung carcinoma includes a series of different diseases which are roughly divided into two groups based on clinical and histo-pathological features: non-small cell lung cancer (NSCLC), accounting for almost 80% of lung cancer diagnosis and small cell lung cancer (SCLC) responsible for the remaining 20%. The NSCLC molecular profile has been deeply investigated; alterations in several oncogenes, tumor suppressor genes and transcription factors have been detected, mainly in adenocarcinomas. Dissection of such a complex scenario represents a still open challenge for both researchers and clinicians. MET, the receptor for Hepatocyte Growth Factor (HGF), has been recently identified as a novel promising target in several human malignancies, including NSCLC. Deregulation of the HGF/MET signaling pathway can occur via different mechanisms, including HGF and/or MET overexpression, MET gene amplification, mutations or rearrangements. While the role of MET mutations in NSCLC is not yet fully understood, MET amplification emerged as a critical event in driving cell survival, with preclinical data suggesting that MET-amplified cell lines are exquisitely sensitive to MET inhibition. True MET amplification, which has been associated with poor prognosis in different retrospective series, is a relatively uncommon event in NSCLC, occurring in 1-7% of unselected cases. Nevertheless, in highly selected cohorts of patients, such as those harboring somatic mutations of EGFR with acquired resistance to EGFR tyrosine kinase inhibitors, MET amplification can be observed in up to 20% of cases. Preclinical data suggested that a treatment approach including a combination of EGFR and MET tyrosine kinases could be an effective strategy in this setting and led to the clinical investigation of multiple MET inhibitors in combination with anti-EGFR agents. Results from ongoing and future trials will clarify the role of anti-MET molecules for the treatment of NSCLC and will provide insights into the most appropriate timing for their use. The present review recapitulates the current knowledge on the role of MET signaling in NSCLC mainly focusing on its implications in molecular diagnostic approach and on the novel targeted inhibitors.
    09/2012; 1(3):194-207. DOI:10.3978/j.issn.2218-6751.2012.09.03
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    ABSTRACT: Hepatocyte growth factor (HGF) receptor, also known as Met, is a member of the receptor tyrosine kinase family. The Met-HGF interaction regulates various signalling pathways involving downstream kinases, such as Akt and Erk. Met activation is implicated in wound healing of tissues via multiple biological responses triggered by the above-mentioned signalling cascade. Here we report the development of artificial Met-activating dimeric macrocycles. We identify Met-binding monomeric macrocyclic peptides by means of the RaPID (random non-standard peptide integrated discovery) system, and dimerize the respective monomers through rational design. These dimeric macrocycles specifically and strongly activate Met signalling pathways through receptor dimerization and induce various HGF-like cellular responses, such as branching morphogenesis, in human cells. This work suggests our approach for generating dimeric macrocycles as non-protein ligands for cell surface receptors can be useful for developing potential therapeutics with a broad range of potential applications.
    Nature Communications 03/2015; 6:6373. DOI:10.1038/ncomms7373 · 10.74 Impact Factor

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