Pathways Downstream of Shc and Grb2 Are Required for Cell Transformation by the Tpr-Met Oncoprotein

Fixman, Elizabeth D.; Fournier, Tanya M.; Kamikura, Darren M.; Naujokas, Monica A.; Park, Morag

doi:10.1074/jbc.271.22.13116

Cited by 136 publications

(172 citation statements)

References 52 publications

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“…Accordingly, the constitutively active oncogenic counterpart of the Met receptor (Tpr ± Met) transforms ®broblasts at high e ciency, and renders them highly metastatic (Park et al, 1986;Giordano et al, 1997). Met signaling and transformation depend on ligand-induced phosphorylation of two carboxy-terminal docking sites of mixed speci®city (Y 1349 /VHVNATY 1356 /VNV, Ponzetto et al, 1994;Fixman et al, 1995;Maina et al, 1996). These phosphotyrosines are responsible for recruiting a number of SH2-containing e ectors, including p85 (the regulatory subunit of PI 3-kinase) and the Grb2 adaptor (Ponzetto et al, 1994).…”

Section: Discussionmentioning

confidence: 99%

“…Dimerization causes constitutive activation of the Met kinase, which acquires transforming and metastatic properties (Park et al, 1986;Giordano et al, 1997). Met signaling and Tpr ± Met mediated transformation are based on the activation of multiple pathways triggered by phosphorylation of two carboxy-terminal tyrosines (Y 1349 VHVNATY 1356 VNV, Ponzetto et al, 1993Ponzetto et al, , 1994Fixman et al, 1995). These tyrosine residues are part of a consensus sequence (YVH/NV) which mediates coupling of the receptor with several e ectors, including the Grb2/SoS complex (Ponzetto et al, 1994;Fixman et al, 1995), the p85 regulatory subunit of PI-3-kinase (Ponzetto et al, 1993), Stat-3 (Boccaccio et al, 1998), and the multiadaptor protein Gab1 (Weidner et al, 1996;Bardelli et al, 1997b;Nguyen et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

“…Met signaling and Tpr ± Met mediated transformation are based on the activation of multiple pathways triggered by phosphorylation of two carboxy-terminal tyrosines (Y 1349 VHVNATY 1356 VNV, Ponzetto et al, 1993Ponzetto et al, , 1994Fixman et al, 1995). These tyrosine residues are part of a consensus sequence (YVH/NV) which mediates coupling of the receptor with several e ectors, including the Grb2/SoS complex (Ponzetto et al, 1994;Fixman et al, 1995), the p85 regulatory subunit of PI-3-kinase (Ponzetto et al, 1993), Stat-3 (Boccaccio et al, 1998), and the multiadaptor protein Gab1 (Weidner et al, 1996;Bardelli et al, 1997b;Nguyen et al, 1997). Grb2, in particular, requires an Asn in the +2 position for binding, and is thus linked to the receptor via the Y 1356 VNV motif Maina et al, 1996;Fixman et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 1999

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The Met tyrosine kinase ± the HGF receptor ± induces cell transformation and metastasis when constitutively activated. Met signaling is mediated by phosphorylation of two carboxy-terminal tyrosines which act as docking sites for a number of SH2-containing molecules. These include Grb2 and p85 which couple the receptor, respectively, with Ras and PI 3-kinase. We previously showed that a Met mutant designed to obtain preferential coupling with Grb2 (Met 2xGrb2 ) is permissive for motility, increases transformation, but ± surprisingly ± is impaired in causing invasion and metastasis. In this work we used Met mutants optimized for binding either p85 alone (Met 2xPI3K ) or p85 and Grb2 (Met P13K/Grb2 ) to evaluate the relative importance of Ras and PI 3-kinase as downstream e ectors of Met. Met 2xPI3K was competent in eliciting motility, but not transformation, invasion, or metastasis. Conversely, Met P13K/Grb2 induced motility, transformation, invasion and metastasis as e ciently as wild type Met. Furthermore, the expression of constitutively active PI 3-kinase in cells transformed by the Met 2xGrb2 mutant, fully rescued their ability to invade and metastasize. These data point to a central role for PI 3-kinase in Met-mediated invasiveness, and indicate that simultaneous activation of Ras and PI 3-kinase is required to unleash the Met metastatic potential.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 1999

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“…The promiscuous docking motif in the C-terminal tail of MET binds numerous Src-homology-2 domain (SH2 domain)-containing effectors, such as PI3K 37 , the non-receptor tyrosine kinase Src 37 , the growth factor receptor-bound protein 2 (GRB2) and SH2 domain-containing transforming protein (SHC) adaptors 37,45,46 , SHP2 (also known as PTPN11; an upstream activator of Src and Ras) 46 , phospholipase Cγ1 (PLCγ1) 37 and the transcription factor STAT3 (Refs 47,48). MET also associates with GRB2-associated-binding protein 1 (GAB1), a multi-adaptor protein that, upon phosphorylation by the MET receptor, provides extra binding sites for SHC, PI3K, SHP2, CRK, PLCγ1 and p120 Ras-GTPase-activating protein (p120-Ras-GAP) 43,44,49,50,51,52,53 .…”

Section: Introductionmentioning

confidence: 99%

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

Trusolino

Bertotti

Comoglio

2010

Nat Rev Mol Cell Biol

1,083

1,076

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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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“…In particular, Tyr 489 represents a multisubstrate binding site for Grb-2, Phospholipase-Cg (PLC-g), tyrosine phosphatase SHP-2, shc, Phosphatidyl Inositol-3 kinase (PI3K), Cbl and Gab-1 (for a review see Bardelli et al, 1997a). Phosphorylation of this site is critical for e cient cellular transformation mediated by Tpr-Met Fixman et al, 1995Fixman et al, , 1997.…”

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confidence: 99%

Loss of the exon encoding the juxtamembrane domain is essential for the oncogenic activation of TPR-MET

et al. 1999

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Pathways Downstream of Shc and Grb2 Are Required for Cell Transformation by the Tpr-Met Oncoprotein

Cited by 136 publications

References 52 publications

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

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

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

Loss of the exon encoding the juxtamembrane domain is essential for the oncogenic activation of TPR-MET

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