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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 interacts with pVEGFR-2 in vitro and in vivo(A) EMMPRIN interacts with pVEGFR-2 in HMEC endothelial cells and M10 tumor cells. In situ PLA for EMMPRIN/pVEGFR-2 was performed after VEGF stimulation (5 minutes, 50 ng/ml); red dots represent EMMPRIN-pVEGFR-2 interaction; nuclei are stained with DAPI (blue). 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. **P ≤ 0.001. (B) EMMPRIN interacts with pVEGFR-2 in human cancer tissues. In situ PLA detection of EMMPRIN and pVEGFR-2 interaction in human melanoma tissues (M202 and M165) and in human breast cancer tissues (B132 and B18) using antibodies against EMMPRIN and pVEGFR-2. Nuclei were stained with DAPI (blue); phase contrast indicates cell contour (grey); the panels show high magnification (x 40) to clearly visualize the PLA spots representing heterodimers. Representative photos of three independent experiments are shown.
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Figure 3: EMMPRIN interacts with pVEGFR-2 in vitro and in vivo(A) EMMPRIN interacts with pVEGFR-2 in HMEC endothelial cells and M10 tumor cells. In situ PLA for EMMPRIN/pVEGFR-2 was performed after VEGF stimulation (5 minutes, 50 ng/ml); red dots represent EMMPRIN-pVEGFR-2 interaction; nuclei are stained with DAPI (blue). 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. **P ≤ 0.001. (B) EMMPRIN interacts with pVEGFR-2 in human cancer tissues. In situ PLA detection of EMMPRIN and pVEGFR-2 interaction in human melanoma tissues (M202 and M165) and in human breast cancer tissues (B132 and B18) using antibodies against EMMPRIN and pVEGFR-2. Nuclei were stained with DAPI (blue); phase contrast indicates cell contour (grey); the panels show high magnification (x 40) to clearly visualize the PLA spots representing heterodimers. Representative photos of three independent experiments are shown.

Mentions: We have next shown that EMMPRIN also interacted with the active form of VEGFR-2 and this interaction was enhanced after VEGF treatment of endothelial as well as melanoma cells. EMMPRIN/pVEGFR-2 heterodimers are visualized by PLA red dots in Figure 3A. Importantly, intense clustering pattern of these EMMPRIN/pVEGFR-2 heterocomplexes were also observed in human breast cancer (n = 11) and melanoma (n = 15) tissues (Figure 3B) demonstrating the implication of EMMPRIN/pVEGFR-2 interactions in vivo.


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 interacts with pVEGFR-2 in vitro and in vivo(A) EMMPRIN interacts with pVEGFR-2 in HMEC endothelial cells and M10 tumor cells. In situ PLA for EMMPRIN/pVEGFR-2 was performed after VEGF stimulation (5 minutes, 50 ng/ml); red dots represent EMMPRIN-pVEGFR-2 interaction; nuclei are stained with DAPI (blue). 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. **P ≤ 0.001. (B) EMMPRIN interacts with pVEGFR-2 in human cancer tissues. In situ PLA detection of EMMPRIN and pVEGFR-2 interaction in human melanoma tissues (M202 and M165) and in human breast cancer tissues (B132 and B18) using antibodies against EMMPRIN and pVEGFR-2. Nuclei were stained with DAPI (blue); phase contrast indicates cell contour (grey); the panels show high magnification (x 40) to clearly visualize the PLA spots representing heterodimers. Representative photos of three independent experiments are shown.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4496396&req=5

Figure 3: EMMPRIN interacts with pVEGFR-2 in vitro and in vivo(A) EMMPRIN interacts with pVEGFR-2 in HMEC endothelial cells and M10 tumor cells. In situ PLA for EMMPRIN/pVEGFR-2 was performed after VEGF stimulation (5 minutes, 50 ng/ml); red dots represent EMMPRIN-pVEGFR-2 interaction; nuclei are stained with DAPI (blue). 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. **P ≤ 0.001. (B) EMMPRIN interacts with pVEGFR-2 in human cancer tissues. In situ PLA detection of EMMPRIN and pVEGFR-2 interaction in human melanoma tissues (M202 and M165) and in human breast cancer tissues (B132 and B18) using antibodies against EMMPRIN and pVEGFR-2. Nuclei were stained with DAPI (blue); phase contrast indicates cell contour (grey); the panels show high magnification (x 40) to clearly visualize the PLA spots representing heterodimers. Representative photos of three independent experiments are shown.
Mentions: We have next shown that EMMPRIN also interacted with the active form of VEGFR-2 and this interaction was enhanced after VEGF treatment of endothelial as well as melanoma cells. EMMPRIN/pVEGFR-2 heterodimers are visualized by PLA red dots in Figure 3A. Importantly, intense clustering pattern of these EMMPRIN/pVEGFR-2 heterocomplexes were also observed in human breast cancer (n = 11) and melanoma (n = 15) tissues (Figure 3B) demonstrating the implication of EMMPRIN/pVEGFR-2 interactions in vivo.

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