Center for Molecular Biology and Genetics of Neurodegeneration, Departments of Psychiatry and Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Cell Mol Life Sci. 2018 Aug;75(15):2813-2826. doi: 10.1007/s00018-018-2762-7. Epub 2018 Feb 10.
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.
早老素 1 基因（PS1）编码 γ-分泌酶的催化亚基，后者能对几种Ⅰ型跨膜蛋白进行蛋白水解加工。我们在此提供的证据表明，早老素 1/γ-分泌酶对 efnB2 配体的裂解产生的胞质肽 efnB2/CTF2 可促进 EphB4 受体依赖性血管生成。EfnB2/CTF2 可增加内皮细胞出芽和管腔形成，刺激包括 VE-钙黏蛋白、Raf-1 和 Rok-α 在内的血管生成复合物的形成，并增加 MLC2 磷酸化。这些功能由 efnB2 的 PDZ 结合域介导。PS1 的急性下调或 γ-分泌酶抑制可抑制 EphB4 的血管生成功能，而 PS1 的缺失则会减少小鼠脑中的 VE-钙黏蛋白血管生成复合物。我们的数据揭示了 PS1/γ-分泌酶调节 efnB2/EphB4 介导的血管生成的机制。
