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EMMPRIN/CD147 is a novel coreceptor of VEGFR-2 mediating its activation by VEGF.

Khayati F, Pérez-Cano L, Maouche K, Sadoux A, Boutalbi Z, Podgorniak MP, Maskos U, Setterblad N, Janin A, Calvo F, Lebbé C, Menashi S, Fernandez-Recio J, Mourah S - Oncotarget (2015)

Bottom Line: EMMPRIN/CD147 is mainly known for its protease inducing function but a role in promoting tumor angiogenesis has also been demonstrated.This study provides evidence that EMMPRIN is a new coreceptor for the VEGFR-2 tyrosine kinase receptor in both endothelial and tumor cells, as it directly interacts with it and regulates its activation by its VEGF ligand, signalling and functional consequences both in vitro and in vivo.EMMPRIN is overexpressed in cancer and hence is able to further potentiate VEGFR-2 activation, suggesting that a combinatory therapy of an antiangiogenic drug together with an inhibitor of EMMPRIN/VEGFR-2 interaction may have a greater impact on inhibiting angiogenesis and malignancy.

View Article: PubMed Central - PubMed

Affiliation: INSERM UMR-S 976, Hôpital Saint-Louis, Paris, France.

ABSTRACT
EMMPRIN/CD147 is mainly known for its protease inducing function but a role in promoting tumor angiogenesis has also been demonstrated. This study provides evidence that EMMPRIN is a new coreceptor for the VEGFR-2 tyrosine kinase receptor in both endothelial and tumor cells, as it directly interacts with it and regulates its activation by its VEGF ligand, signalling and functional consequences both in vitro and in vivo. Computational docking analyses and mutagenesis studies identified a molecular binding site in the extracellular domain of EMMPRIN located close to the cell membrane and containing the amino acids 195/199. EMMPRIN is overexpressed in cancer and hence is able to further potentiate VEGFR-2 activation, suggesting that a combinatory therapy of an antiangiogenic drug together with an inhibitor of EMMPRIN/VEGFR-2 interaction may have a greater impact on inhibiting angiogenesis and malignancy.

No MeSH data available.


Related in: MedlinePlus

EMMPRIN amino acid residues 195–199 are required for EMMPRIN/pVEGFR-2 interactionEMMPRIN/VEGFR-2 interaction in BLM EMMPRIN-deficient cells transfected with EMMPRIN simple and double mutant constructs, control D136A and WT. After VEGFR-2 pull-downs, interaction with EMMPRIN was analyzed by Western blotting. Representative blots of three independent experiments are shown. In situ PLA using confocal microscopy shows red fluorescent spots which denote very close localization between EMMPRIN and pVEGFR-2. Fluorescence was markedly decreased with the double mutant Q195A/T199A. Nuclei were stained with DAPI (blue), magnification x 63. Representative images of three independent experiments are shown. Quantification of PLA signals was performed on ~150 transfected cells per condition in three independent experiments; mean PLA signal/cell ± SD are plotted.
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Figure 8: EMMPRIN amino acid residues 195–199 are required for EMMPRIN/pVEGFR-2 interactionEMMPRIN/VEGFR-2 interaction in BLM EMMPRIN-deficient cells transfected with EMMPRIN simple and double mutant constructs, control D136A and WT. After VEGFR-2 pull-downs, interaction with EMMPRIN was analyzed by Western blotting. Representative blots of three independent experiments are shown. In situ PLA using confocal microscopy shows red fluorescent spots which denote very close localization between EMMPRIN and pVEGFR-2. Fluorescence was markedly decreased with the double mutant Q195A/T199A. Nuclei were stained with DAPI (blue), magnification x 63. Representative images of three independent experiments are shown. Quantification of PLA signals was performed on ~150 transfected cells per condition in three independent experiments; mean PLA signal/cell ± SD are plotted.

Mentions: We first transfected BLM-EMMPRIN-miRNA cells with EMMPRIN full length cDNA (wide type: WT) or mutated on the following residues: D136A, D144A, Q182A, R184A, Q195A, T199A, Q182A/R184A and Q195A/T199A. EMMPRIN/VEGFR-2 binding was evaluated by immunoprecipitation using an antibody directed against VEGFR-2 (Figure 8). Results show that both the single and the double mutants reduced EMMPRIN/VEGFR-2 binding to a varying degrees but the greatest reduction was observed with the double mutant Q195A/T199A pointing to the importance of this site in the interaction. By contrast, the negative control D136A mutant had no detectable effect on EMMPRIN/VEGFR-2 binding.


EMMPRIN/CD147 is a novel coreceptor of VEGFR-2 mediating its activation by VEGF.

Khayati F, Pérez-Cano L, Maouche K, Sadoux A, Boutalbi Z, Podgorniak MP, Maskos U, Setterblad N, Janin A, Calvo F, Lebbé C, Menashi S, Fernandez-Recio J, Mourah S - Oncotarget (2015)

EMMPRIN amino acid residues 195–199 are required for EMMPRIN/pVEGFR-2 interactionEMMPRIN/VEGFR-2 interaction in BLM EMMPRIN-deficient cells transfected with EMMPRIN simple and double mutant constructs, control D136A and WT. After VEGFR-2 pull-downs, interaction with EMMPRIN was analyzed by Western blotting. Representative blots of three independent experiments are shown. In situ PLA using confocal microscopy shows red fluorescent spots which denote very close localization between EMMPRIN and pVEGFR-2. Fluorescence was markedly decreased with the double mutant Q195A/T199A. Nuclei were stained with DAPI (blue), magnification x 63. Representative images of three independent experiments are shown. Quantification of PLA signals was performed on ~150 transfected cells per condition in three independent experiments; mean PLA signal/cell ± SD are plotted.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Figure 8: EMMPRIN amino acid residues 195–199 are required for EMMPRIN/pVEGFR-2 interactionEMMPRIN/VEGFR-2 interaction in BLM EMMPRIN-deficient cells transfected with EMMPRIN simple and double mutant constructs, control D136A and WT. After VEGFR-2 pull-downs, interaction with EMMPRIN was analyzed by Western blotting. Representative blots of three independent experiments are shown. In situ PLA using confocal microscopy shows red fluorescent spots which denote very close localization between EMMPRIN and pVEGFR-2. Fluorescence was markedly decreased with the double mutant Q195A/T199A. Nuclei were stained with DAPI (blue), magnification x 63. Representative images of three independent experiments are shown. Quantification of PLA signals was performed on ~150 transfected cells per condition in three independent experiments; mean PLA signal/cell ± SD are plotted.
Mentions: We first transfected BLM-EMMPRIN-miRNA cells with EMMPRIN full length cDNA (wide type: WT) or mutated on the following residues: D136A, D144A, Q182A, R184A, Q195A, T199A, Q182A/R184A and Q195A/T199A. EMMPRIN/VEGFR-2 binding was evaluated by immunoprecipitation using an antibody directed against VEGFR-2 (Figure 8). Results show that both the single and the double mutants reduced EMMPRIN/VEGFR-2 binding to a varying degrees but the greatest reduction was observed with the double mutant Q195A/T199A pointing to the importance of this site in the interaction. By contrast, the negative control D136A mutant had no detectable effect on EMMPRIN/VEGFR-2 binding.

Bottom Line: EMMPRIN/CD147 is mainly known for its protease inducing function but a role in promoting tumor angiogenesis has also been demonstrated.This study provides evidence that EMMPRIN is a new coreceptor for the VEGFR-2 tyrosine kinase receptor in both endothelial and tumor cells, as it directly interacts with it and regulates its activation by its VEGF ligand, signalling and functional consequences both in vitro and in vivo.EMMPRIN is overexpressed in cancer and hence is able to further potentiate VEGFR-2 activation, suggesting that a combinatory therapy of an antiangiogenic drug together with an inhibitor of EMMPRIN/VEGFR-2 interaction may have a greater impact on inhibiting angiogenesis and malignancy.

View Article: PubMed Central - PubMed

Affiliation: INSERM UMR-S 976, Hôpital Saint-Louis, Paris, France.

ABSTRACT
EMMPRIN/CD147 is mainly known for its protease inducing function but a role in promoting tumor angiogenesis has also been demonstrated. This study provides evidence that EMMPRIN is a new coreceptor for the VEGFR-2 tyrosine kinase receptor in both endothelial and tumor cells, as it directly interacts with it and regulates its activation by its VEGF ligand, signalling and functional consequences both in vitro and in vivo. Computational docking analyses and mutagenesis studies identified a molecular binding site in the extracellular domain of EMMPRIN located close to the cell membrane and containing the amino acids 195/199. EMMPRIN is overexpressed in cancer and hence is able to further potentiate VEGFR-2 activation, suggesting that a combinatory therapy of an antiangiogenic drug together with an inhibitor of EMMPRIN/VEGFR-2 interaction may have a greater impact on inhibiting angiogenesis and malignancy.

No MeSH data available.


Related in: MedlinePlus