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

• Published in: Cellular and molecular life sciences : CMLS Vol. 75; no. 15; pp. 2813 - 2826
• Main Authors: Warren, Noel A., Voloudakis, Georgios, Yoon, Yonejung, Robakis, Nikolaos K., Georgakopoulos, Anastasios
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.08.2018; Springer Nature B.V
• Subjects: Amyloid Precursor Protein Secretases - antagonists & inhibitors; Amyloid Precursor Protein Secretases - genetics; Amyloid Precursor Protein Secretases - metabolism; Angiogenesis; Animals; Antigens, CD - metabolism; Biochemistry; Biomedical and Life Sciences; Biomedicine; Brain; Cadherins; Cadherins - metabolism; Catalysis; Cattle; Cell Biology; Cells, Cultured; Endothelial cells; Endothelial Cells - drug effects; Endothelial Cells - metabolism; Endothelial Cells - physiology; Enzyme Inhibitors - pharmacology; Ephrin-B2 - metabolism; Life Sciences; Membrane proteins; Mice, Knockout; Microscopy, Confocal; Neovascularization, Physiologic - drug effects; Original Article; Peptides - metabolism; Peptides - pharmacology; Phosphorylation; Presenilin 1; Proteins; Receptor, EphB4 - metabolism; RNA Interference; Secretase; EphrinB2; Angiogenesis; γ-Secretase; Presenilin1; VE-cadherin
• ISSN: 1420-682X; 1420-9071
• DOI: 10.1007/s00018-018-2762-7

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.