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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 VEGF-mediated VEGFR-2 activationVEGF-mediated VEGFR-2 phosphorylation in BLM EMMPRIN-deficient cells transfected with EMMPRIN double mutant constructs, control D136A and WT. VEGFR-2 phosphorylation by VEGF (5 min) was analyzed by VEGFR-2 IP followed by immunoblotting for pVEGFR-2 and VEGFR-2. Representative blots of three independent experiments are shown. In situ PLA was performed to identify VEGF/pVEGFR-2 interaction (red dots) with and without VEGF treatment. Nuclei are 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. Comparing PLA signals between VEGF treated and non-treated showed significant difference for WT and control conditions; **P ≤ 0.001.
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Figure 9: EMMPRIN amino acid residues 195–199 are required for VEGF-mediated VEGFR-2 activationVEGF-mediated VEGFR-2 phosphorylation in BLM EMMPRIN-deficient cells transfected with EMMPRIN double mutant constructs, control D136A and WT. VEGFR-2 phosphorylation by VEGF (5 min) was analyzed by VEGFR-2 IP followed by immunoblotting for pVEGFR-2 and VEGFR-2. Representative blots of three independent experiments are shown. In situ PLA was performed to identify VEGF/pVEGFR-2 interaction (red dots) with and without VEGF treatment. Nuclei are 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. Comparing PLA signals between VEGF treated and non-treated showed significant difference for WT and control conditions; **P ≤ 0.001.

Mentions: The role of these EMMPRIN residues on the activation of VEGFR-2 by its ligand VEGF was investigated by studying the binding behaviour of the EMMPRIN mutants towards VEGF-induced VEGFR-2 activation. Figure 9 shows a total inhibition of pVEGFR-2 activation by VEGF with the double mutant Q195A/T199A while the other single mutants had lower effects (Figure S1). This is consistent with the VEGF/pVEGFR-2 interaction results obtained by in situ PLA.


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 VEGF-mediated VEGFR-2 activationVEGF-mediated VEGFR-2 phosphorylation in BLM EMMPRIN-deficient cells transfected with EMMPRIN double mutant constructs, control D136A and WT. VEGFR-2 phosphorylation by VEGF (5 min) was analyzed by VEGFR-2 IP followed by immunoblotting for pVEGFR-2 and VEGFR-2. Representative blots of three independent experiments are shown. In situ PLA was performed to identify VEGF/pVEGFR-2 interaction (red dots) with and without VEGF treatment. Nuclei are 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. Comparing PLA signals between VEGF treated and non-treated showed significant difference for WT and control conditions; **P ≤ 0.001.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4496396&req=5

Figure 9: EMMPRIN amino acid residues 195–199 are required for VEGF-mediated VEGFR-2 activationVEGF-mediated VEGFR-2 phosphorylation in BLM EMMPRIN-deficient cells transfected with EMMPRIN double mutant constructs, control D136A and WT. VEGFR-2 phosphorylation by VEGF (5 min) was analyzed by VEGFR-2 IP followed by immunoblotting for pVEGFR-2 and VEGFR-2. Representative blots of three independent experiments are shown. In situ PLA was performed to identify VEGF/pVEGFR-2 interaction (red dots) with and without VEGF treatment. Nuclei are 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. Comparing PLA signals between VEGF treated and non-treated showed significant difference for WT and control conditions; **P ≤ 0.001.
Mentions: The role of these EMMPRIN residues on the activation of VEGFR-2 by its ligand VEGF was investigated by studying the binding behaviour of the EMMPRIN mutants towards VEGF-induced VEGFR-2 activation. Figure 9 shows a total inhibition of pVEGFR-2 activation by VEGF with the double mutant Q195A/T199A while the other single mutants had lower effects (Figure S1). This is consistent with the VEGF/pVEGFR-2 interaction results obtained by in situ PLA.

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