Met receptor tyrosine kinase: enhanced signaling through adapter proteins

Furge, Kyle A.; Zhang, Kun; Woude, George F. Vande

doi:10.1038/sj.onc.1203859

Cited by 369 publications

(334 citation statements)

References 108 publications

(108 reference statements)

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“…Exhaustive information on the identities and branches of MET-dependent signalling networks can be found in numerous reviews 22,23,24,25,26,27,28,29 . Here, as well as presenting some basic principles of MET signalling regulation, we consider recent findings that have provided fresh knowledge on this matter at the molecular, cellular and animal levels.…”

Section: Introductionmentioning

confidence: 99%

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

Trusolino

Bertotti

Comoglio

2010

Nat Rev Mol Cell Biol

1,042

1,067

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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.Throughout embryogenesis, cells bud off from developing tissues and move outwards to shape and pattern the complex architecture of prospective organs 1 . A similar process occurs in adult life during wound healing and tissue repair, when lingering cells migrate into injury sites to recreate the pre-existing structures 2 . The acquisition of cell motility is necessary, but not sufficient, for this event. Cells that detach from their neighbours must elude anoikis, a form of apoptotic cell death that occurs when cells lose adhesion with the extracellular matrix 3 . Moreover, migratory cells undergo extensive mitotic divisions to produce 'founder populations', which settle in newly forming organs during development or colonize worn tissues during repair 4,5 . The normal phases of embryogenesis and organ regeneration strongly resemble the pathological process of tumour invasiveness: similarly to cells at the wound edge, cells at the tumour's leading front disrupt intercellular contacts and infiltrate the adjacent surroundings, where they resist anoikis and grow before lodging in the blood vessels for systemic dissemination 6 . This resemblance is not simply a biological correlate, it has a common mechanistic basis: cancer cells resurrect the latent schemes of cellular reorganization, which are usually confined to embryonic development and damaged adult organs, and leverage them to become competent for metastasization 7 . The activities -motility, survival and proliferation -that occur in developing, injured and neoplastic tissues embody a biological programme that is defined as 'invasive growth' 8 . This is triggered by extracellular stimuli that regulate the activity of several transcription factors that, in turn, modulate the expression of a number of proteins, ranging from cytoskeletal and cell-cell junctional components to cell cycle regulators and anti-apoptotic effectors 9, 10 . One major environmental inducer of invasive growth is hepatocyte growth factor (HGF, also known as scatter factor), the ligand for the MET tyrosine kinase receptor (also known as the HGF receptor) 11,12,13,14,15,16,17,18,19,20 (Box 1). ...

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Section: Introductionmentioning

confidence: 99%

“…This is the basic signalling machinery of MET. Further levels of complexity are provided by the interaction of MET with different signal modifiers, including scaffolding adaptors, cytoskeletal connectors and structurally homologous co-receptors 25,26,41 (Fig. 1).…”

mentioning

confidence: 99%

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

Trusolino

Bertotti

Comoglio

2010

Nat Rev Mol Cell Biol

1,042

1,067

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“…Upon binding to its cognate tyrosine kinase receptor, c-Met, HGF activates multiple signaling pathways (4,5), including phosphatidylinositol 3-kinase-Akt, Ras-Mek-Erk, and the Stat3 pathways, and thereby modulates a variety of cell processes, including mitogenesis, motogenesis, morphogenesis, and antiapoptosis/prosurvival in a number of cell types (1)(2)(3)(4)(5)(6)(7). In vivo, HGF has been shown to protect against acute and chronic injury in multiple organ systems, including liver (8), lung (9), intestine (10), and kidney (11).…”

mentioning

confidence: 99%

Hepatocyte Growth Factor Suppresses Proinflammatory NFκB Activation through GSK3β Inactivation in Renal Tubular Epithelial Cells

Gong

Rifai

et al. 2008

Journal of Biological Chemistry

108

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Activation of NF B is a fundamental cellular event central to all inflammatory diseases. Hepatocyte growth factor (HGF) ameliorates both acute and chronic inflammation in a multitude of organ systems through modulating NF B activity; nevertheless, the exact molecular mechanism remains uncertain. Here we report that HGF through inactivation of GSK3␤ suppresses NF B p65 phosphorylation specifically at position Ser-468. The Ser-468 of RelA/p65 situates in a GSK3␤ consensus motif and could be directly phosphorylated by GSK3␤ both in vivo and in vitro, signifying Ser-468 of RelA/p65 as a putative substrate for GSK3␤. In addition, the C terminus of RelA/p65 harbors a highly conserved domain homologue of the consensus docking sequence for GSK3␤. Moreover, this domain was required for efficient phosphorylation of Ser-468 and was indispensable for the physical interaction between RelA/p65 and GSK3␤. HGF substantially intercepted this interaction by inactivating GSK3␤. Functionally, phosphorylation of Ser-468 of RelA/p65 was required for the induced expression of a particular subset of proinflammatory NF B-dependent genes. Diminished phosphorylation at Ser-468 by HGF resulted in a gene-specific inhibition of these genes' expression. The action of HGF on proinflammatory NF B activation was consistently mimicked by a selective GSK3␤ inhibitor or GSK3␤ knockdown by RNA interference but largely abrogated in cells expressing the mutant uninhibitable GSK3␤. Collectively, our findings suggest that HGF has a potent suppressive effect on NF B activation, which is mediated by GSK3␤, an important signaling transducer controlling RelA/p65 phosphorylation specificity and directing the transcription of selective proinflammatory cytokines implicated in inflammatory kidney disease.

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“…Both signalling pathways have a remarkably pleiotropic nature and share common intracellular signalling molecules and biological effects, playing fundamental roles during development and oncogenesis [5][6][7][8]. The HGF actions, namely proliferation, survival, motility, and morphogenesis, are driven by ligand bindingdependent autophosphorylation of c-Met on specific tyrosine residues in the tyrosine kinase and C-terminal domains, followed by either adapter-mediated or direct recruitment and activation of multiple signal transducers, including Ras-ERK 1/2 mitogen activated protein kinases (MAPKs), phosphatidylinositol-3 kinase (PI3K)-AKT, phospholipase C-γ (PLC-γ), p38, and STAT3 [9]. EGF, on the other hand, binds to and activate the EGFR, which is part of a complex signalling system that includes up to 15 different ligands, transforming growth factor alpha activator of transcription-3, TGF-α, transforming growth factor-alpha; TGF-β, transforming growth factor-beta.…”

Section: Introductionmentioning

confidence: 99%

EGFR is dispensable for c-Met-mediated proliferation and survival activities in mouse adult liver oval cells

Martínez-Palacián

Castillo

Herrera

et al. 2012

Cellular Signalling

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Met receptor tyrosine kinase: enhanced signaling through adapter proteins

Cited by 369 publications

References 108 publications

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

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

Hepatocyte Growth Factor Suppresses Proinflammatory NFκB Activation through GSK3β Inactivation in Renal Tubular Epithelial Cells

EGFR is dispensable for c-Met-mediated proliferation and survival activities in mouse adult liver oval cells

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