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

Key Points

  • Hepatocyte growth factor (HGF) and its tyrosine kinase receptor MET (also known as HGF receptor) mediate invasive growth, a complex programme in which cells lose contacts with their neighbours, mobilize towards adjacent surroundings, resist apoptotic insults and proliferate.

  • During development, HGF and MET are essential for the growth and survival of epithelial cell types and for the migration of muscle progenitors. In adult physiology, MET exerts a trophic activity that attenuates tissue damage and promotes the regeneration of several organs.

  • In tumours, MET stimulates the motility and survival of cancer cells as well as angiogenesis, thereby acting as a powerful expedient for neoplastic invasion and production of secondary metastases. MET gain-of-function genetic lesions can also be selected to maintain the transformed phenotype of some primary tumours, which seem to be 'addicted' to continued MET activity for their relentless growth.

  • MET signals are channelled by an unconventional multifunctional docking site consisting of two tyrosines that, when phosphorylated, recruit a wide spectrum of transducers. Interaction with the GRB2-associated-binding protein 1 (GAB1) multi-adaptor protein is critical for transduction of most MET signalling pathways, whereas tissue-specific interactions with other surface partners such as the α6β4 integrin and the CD44 adhesion molecule regulate quantitative modulation of downstream signalling and cytoskeletal compartmentalization, respectively.

  • MET signals emanate not only from the plasma membrane but also from endosomal compartments, and MET internalization seems to be required for efficient activation and proper subcellular localization of distal transducers such as extracellular signal-regulated kinases (ERKs) and signal transducer and activator of transcription 3 (STAT3). MET also undergoes other trafficking events — including extracellular shedding, intracellular cleavage, ubiquitylation, degradation and membrane recycling — which regulate the strength of MET activation and the ensuing robustness of MET-dependent signals.

  • In distinct cells and tissues, specific activities that are controlled by MET seem to be fulfilled by dedicated signalling cascades, with some transducers dominating over others according to context, timing and biological complexity. This suggests that the specificity of MET-dependent responses is determined, at least in part, by qualitative differences in signalling outputs.

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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Figure 1: Signal cooperation between MET pathway components.
Figure 2: Major MET-regulated signalling pathways.
Figure 3: Compartmentalization of MET signals.
Figure 4: The phenotypes of genetic abrogation of specific MET signals.

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Acknowledgements

The authors thank C. Boccaccio and their colleagues of the Laboratory of Molecular Pharmacology at IRCC, Torino, Italy, for comments and suggestions. Work in the authors' laboratory is funded by grants from: Associazione Italiana per la Ricerca sul Cancro (AIRC), Milano, Italy; European Union Framework Programmes; Regione Piemonte, Italy; Ministero dell'Università e della Ricerca, Italy; and Fondazione Piemontese per la Ricerca sul Cancro (FPRC), Italy.

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Glossary

Paracrine

Describing, or relating to, a regulatory cell that secretes a soluble molecule into an intercellular space, from which it diffuses to a nearby target cell other than the one that produces it.

Reactive interstitial compartment

A connective tissue that responds to neighbouring stimuli such as inflammation and tumour formation or invasion.

Src-homology-2 domain

(SH2 domain). A protein module that recognizes and binds tyrosine-phosphorylated sequences in a sequence-specific context and thereby has a key role in relaying cascades of signal transduction.

GTPase-activating protein

(GAP). A protein that stimulates the intrinsic ability of a GTPase to hydrolyse GTP to GDP. GAPs negatively regulate GTPases by converting them from an active (GTP-bound) to an inactive (GDP-bound) state.

Guanine nucleotide exchange factor

A protein that facilitates the exchange of GDP for GTP in the nucleotide-binding pocket of a GTPase.

Pleckstrin homology domain

(PH domain). A protein domain that is characteristic of the RNase PH family of bacterial phosphate-dependent ribonucleases.

Endosomal

Relating to a vesicle formed by invagination of the plasma membrane.

Endocytosis

Internalization and transport of extracellular material and plasma membrane proteins from the cell surface to intracellular organelles known as endosomes.

Focal complex

A small (1 μm diameter), dot-like adhesion structure that is present mainly at the edge of the lamellipodium.

Focal adhesion

A cellular structure that links, through integrin receptors, the extracellular matrix outside the cell to the actin cytoskeleton inside the cell.

E3 ubiquitin-protein ligase

An enzyme that is responsible for the conjugation of ubiquitin to substrate proteins.

Multivesicular body

An endocytic intermediate organelle in the lysosomal degradative pathway that contains small vesicles and is surrounded by a limiting membrane.

Proteasome

A large multisubunit protein complex that degrades unnecessary or damaged proteins by proteolysis.

Placental labyrinth

The area of direct exchange between the fetal and maternal blood supply in the mammalian placenta.

Hypaxial muscle

Skeletal muscle that is derived from progenitor cell populations that are located in the lateral myotome of each somite. Examples of hypaxial muscles include, among others, the diaphragm, the abdominal muscles and the muscles of the limb and girdles.

Epithelial–mesenchymal transition

(EMT). The transformation of an epithelial cell into a mesenchymal cell that has migratory and invasive properties.

Myofibroblast

A modified fibroblast with smooth muscle-like features and contractile properties.

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Trusolino, L., Bertotti, A. & Comoglio, P. MET signalling: principles and functions in development, organ regeneration and cancer. Nat Rev Mol Cell Biol 11, 834–848 (2010). https://doi.org/10.1038/nrm3012

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