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The product of the γ-secretase processing of ephrinB2 regulates VE-cadherin complexes and angiogenesis

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Abstract

Presenilin-1 (PS1) gene encodes the catalytic component of γ-secretase, which proteolytically processes several type I transmembrane proteins. We here present evidence that the cytosolic peptide efnB2/CTF2 produced by the PS1/γ-secretase cleavage of efnB2 ligand promotes EphB4 receptor-dependent angiogenesis in vitro. EfnB2/CTF2 increases endothelial cell sprouting and tube formation, stimulates the formation of angiogenic complexes that include VE-cadherin, Raf-1 and Rok-α, and increases MLC2 phosphorylation. These functions are mediated by the PDZ-binding domain of efnB2. Acute downregulation of PS1 or inhibition of γ-secretase inhibits the angiogenic functions of EphB4 while absence of PS1 decreases the VE-cadherin angiogenic complexes of mouse brain. Our data reveal a mechanism by which PS1/γ-secretase regulates efnB2/EphB4 mediated angiogenesis.

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Abbreviations

EfnB2:

EphrinB2

CTF2:

Carboxy terminal fragment 2

CTF1:

Carboxy terminal fragment 1

PS1:

Presenilin1

WT:

Wild type

KO:

Knockout

VE-cadherin:

Vascular Endothelial cadherin

N-cad:

Neuronal cadherin

Rap1:

Ras-proximate-1 or Ras-related protein 1

Rok-α:

Rho-associated, coiled-coil-containing protein kinase 2

BAMEC:

Bovine adrenal microvessel endothelial cells

MLC2:

Myosin light chain 2

FAD:

Familial Alzheimer’s disease

AD:

Alzheimer’s disease

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Acknowledgements

This work was supported by NIH Grants 2R01-NS047229-11, P50AG05138, AG-17926, AG-008200 and by Alzheimer’s Association Grant IIRG-11-205149.

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Authors and Affiliations

  1. Center for Molecular Biology and Genetics of Neurodegeneration, Departments of Psychiatry and Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Noel A. Warren, Georgios Voloudakis, Yonejung Yoon, Nikolaos K. Robakis & Anastasios Georgakopoulos

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  1. Noel A. Warren
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  2. Georgios Voloudakis
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  3. Yonejung Yoon
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  5. Anastasios Georgakopoulos
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Contributions

AG conceived the project, designed the research, supervised the project and wrote the manuscript with input from all authors. NW, GV, YY performed experiments and contributed to writing of the manuscript. NR supervised the work and contributed to research design and writing of the manuscript.

Corresponding author

Correspondence to Anastasios Georgakopoulos.

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Warren, N., Voloudakis, G., Yoon, Y. et al. The product of the γ-secretase processing of ephrinB2 regulates VE-cadherin complexes and angiogenesis. Cell. Mol. Life Sci. 75, 2813–2826 (2018). https://doi.org/10.1007/s00018-018-2762-7

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