Regulation of the urokinase-type plasminogen activator gene by the oncogene Tpr-Met involves GRB2

Besser, Daniel; Bardelli, Alberto; Didichenko, Svetlana A.; Thelen, Marcus; Comoglio, Paolo M.; Ponzetto, Carola; Nagamine, Yoshikuni

doi:10.1038/sj.onc.1200879

Cited by 47 publications

(35 citation statements)

References 27 publications

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“…The Tpr ± Met 2xPI3K mutant, Tpr ± Met Grb27 , as well as Tpr ± Met Double do not associate Grb2. In agreement with these associations data we have shown that Tpr ± Met 2xGrb2 elicits an increased response with respect to Tpr ± Met Wt from a Ras-responsive promoter, while the ability of Tpr ± Met 2xPI3K and of Tpr ± Met Grb27 to elicit a Ras-mediated response is impaired (Besser et al, 1997). For PI 3-kinase, lysates of COS-1 cells transfected with the various Tpr ± Met mutants were immunoprecipitated with anti-Met antibodies and blotted with antibodies speci®c for p85.…”

Section: Construction Of Tpr ± Met Signaling Mutantssupporting

confidence: 89%

“…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). While p85 binds at low a nity to either site, Grb2 binds at high a nity to Y 1356 VNV, and links the receptor directly to the Ras pathway via the Grb2/SoS complex (Ponzetto et al, 1993(Ponzetto et al, , 1994Fixman et al, 1997 (Besser et al, 1997) and was more transforming than wild type . However, cells transformed by this mutant were impaired in their ability to invade extra-cellular matrices in vitro and to induce metastasis in nude mice (Giordano et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

“…Recently, expression of constitutively activated PI 3-kinase has been shown to be su cient to cause scattering in MDCK cells, provided that a basal level of MAP kinase activity is present (Khwaja et al, 1998). We have previously shown that the Tpr ± Met 2xPI3K mutant elicits from a Ras responsive promoter a response which is 25% of wild type (Besser et al, 1997). This threshold of Ras signaling combined with Met-mediated PI 3-kinase activation is thus su cient to confer motility to epithelial cells.…”

Section: Discussionmentioning

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: Construction Of Tpr ± Met Signaling Mutantssupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

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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“…[27][28][29] Interestingly, uPA activates pro-HGF in vitro, and activation of pro-HGF involves the formation of a stable complex between pro-HGF and uPA, 29 suggesting that the biological effects of HGF can be titrated in vivo by the level of uPA activity. Increased amounts of uPA locally induced by HGF may condition the tissue microenvironment by rendering HGF bioavailable to its target cells.…”

Section: Figure 7 Effect Of Transfection Of Human Hgf Plasmid On Percmentioning

confidence: 99%

Therapeutic angiogenesis induced by human hepatocyte growth factor gene in rat and rabbit hindlimb ischemia models: preclinical study for treatment of peripheral arterial disease

et al. 2001

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Hepatocyte growth factor (HGF) exclusively stimulates the growth of endothelial cells without replication of vascular smooth muscle cells, and acts as a survival factor against endothelial cell death. Recently, a novel therapeutic strategy for ischemic diseases using angiogenic growth factors to expedite and/or augment collateral artery development has been proposed. We have previously reported that intraarterial administration of recombinant HGF induced angiogenesis in a rabbit hindlimb ischemia model. In this study, we examined the feasibility of gene therapy using HGF to treat peripheral arterial disease rather than recombinant therapy, due to its disadvantages. Initially, we examined the transfection of 'naked' human HGF plasmid into a rat hindlimb ischemia model. Intramuscular injection of human HGF plasmid resulted in a significant increase in blood flow as assessed by laser Doppler imaging, accompanied by the detection of human HGF protein. A significant increase in capillary density was found in rats transfected with human HGF as compared with control vector, in a dose-dependent manner (P Ͻ 0.01). Importantly, at 5 weeks after transfection, the degree of angiogenesis induced by transfection of HGF plasmid was significantly greater than that caused by

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“…39 Met is expressed in podocytes. 40,41 Met activation leads to phosphorylation of downstream mediators AKT 42 and extracellular signalregulated kinase (ERK), 43 which are both known to have antiapoptotic effects in general 44 and also in podocytes. 45,46 The present study tests the hypothesis that podocytopenia occurs in TxG and that disruption of the antiapoptotic HGF signal from GECs to podocytes is a possible cause of this podocytopenia.…”

Section: Transplant Glomerulopathy (Txg) Can Show Secondary Focal Andmentioning

confidence: 99%

Diminished Met Signaling in Podocytes Contributes to the Development of Podocytopenia in Transplant Glomerulopathy

Agustian

Schiffer

Gwinner

et al. 2011

The American Journal of Pathology

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Regulation of the urokinase-type plasminogen activator gene by the oncogene Tpr-Met involves GRB2

Cited by 47 publications

References 27 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

Therapeutic angiogenesis induced by human hepatocyte growth factor gene in rat and rabbit hindlimb ischemia models: preclinical study for treatment of peripheral arterial disease

Diminished Met Signaling in Podocytes Contributes to the Development of Podocytopenia in Transplant Glomerulopathy

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