Concomitant activation of pathways downstream of Grb2 and PI 3-kinase is required for MET-mediated metastasis

Bardelli, Alberto; Basile, Maria Lisa; Audero, Enrica; Giordano, Silvia; Wennström, Stefan; Ménard, Sylvie; Comoglio, Paolo M.; Ponzetto, Carola

doi:10.1038/sj.onc.1202607

Cited by 74 publications

(56 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This provides a mechanism for Ron activation by HGF in the case of MSP de®ciency during embryonic development. The response to HGF and MSP through the activation of Met and Ron is mediated by the same pathways, mainly by Ras and by PI-3 Kinase (Wang et al, 1996;Bardelli et al, 1999). Met can regulate growth and transformation by activating the MAP kinase cascade through Grb2/Sos/Ras complex whereas the Ron pathway is directed more towards cellular movement and matrix invasion (Santoro et al, 1996;Wang et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

Cross-talk between the proto-oncogenes Met and Ron

et al. 2000

View full text Add to dashboard Cite

Section: Discussionmentioning

confidence: 99%

Cross-talk between the proto-oncogenes Met and Ron

et al. 2000

View full text Add to dashboard Cite

“…In spite of the high levels of MET, our inducible system led to a strong decrease of both MET mRNA (Supplementary Figure 1b) and protein (Figure 2a,upper panel) in the presence of doxycycline. On MET silencing, we also observed impairment in activation of p42/44 mitogen-activated protein kinase (MAPK) and AKT, two downstream effectors of MET involved in the invasive (Grotegut et al, 2006) and anti-apoptotic response, respectively (Bardelli et al, 1999;Figure 2a).…”

Section: Met Silencing Inhibits Invasive Growth 'In Vitro'mentioning

confidence: 95%

Silencing the MET oncogene leads to regression of experimental tumors and metastases

et al. 2007

View full text Add to dashboard Cite

In spite of the established knowledge of the genetic alterations responsible for cancer onset, the genes promoting and maintaining the invasive/metastatic phenotype are still elusive. The MET proto-oncogene, encoding the tyrosine kinase receptor for hepatocyte growth factor (HGF), senses unfavorable micro-environmental conditions and drives cell invasion and metastasis. MET overexpression, often induced by tumor hypoxia, leads to constitutive activation of the receptor and correlates with poor prognosis. To establish the role of MET in different phases of tumor progression, we developed an inducible lentiviral delivery system of RNA interference. Silencing the endogenous MET gene, overexpressed in tumor cells, resulted in (i) impairment of the execution of the full invasive growth program in vitro, (ii) lack of tumor growth and (iii) decreased generation of experimental metastases in vivo. Notably, silencing MET in already established metastases led to their almost complete regression. This indicates that persistent expression of the MET oncogene is mandatory until the advanced phases of cancer progression.

show abstract

“…The contribution of specific signals to MET activity in tumours has been partially dissected through the manipulation of the consensus sequences that mediate the recruitment of distinct transducers. By converting the multifunctional docking site of an oncogenic mutant of MET into preferential binding motifs for GRB2 or PI3K, it was demonstrated that Ras signals are primarily involved in MET-triggered cell proliferation, whereas PI3K recruitment is required for the induction of cell motility and invasion; however, a fully metastatic phenotype can be recapitulated only when both effectors are concomitantly associated with MET 137,138 . Thus, combined activation of multiple pathways is necessary to instruct the full execution of MET-dependent invasive growth in cancer cells.…”

Section: Met Signalling In Development and Diseasementioning

confidence: 99%

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

Trusolino

Bertotti

Comoglio

2010

Nat Rev Mol Cell Biol

1,060

1,076

View full text Add to dashboard Cite

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). ...

show abstract

Concomitant activation of pathways downstream of Grb2 and PI 3-kinase is required for MET-mediated metastasis

Cited by 74 publications

References 45 publications

Cross-talk between the proto-oncogenes Met and Ron

Cross-talk between the proto-oncogenes Met and Ron

Silencing the MET oncogene leads to regression of experimental tumors and metastases

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

Contact Info

Product

Resources

About