ROLE OF PS1/Y-SECRETASE IN THE ANGIOGENIC PROPERTIES OF EPHRINB/EphB

阿尔茨海默病（AD）是一种以严重神经血管功能障碍为特征的神经退行性疾病。越来越多的证据表明，大脑微血管异常在AD神经病理的发生。早老素1 （PS1）是一种对阿尔茨海默病的神经病理至关重要的蛋白。这种蛋白的突变与许多常染色体显性形式的阿尔茨海默病有关。PS1控制y分泌酶切割几种I型跨膜蛋白，产生具有信号传导和基因表达功能的胞质肽。我们最近发现PS1/y分泌酶可切割ephrinB蛋白并促进ephb诱导的Src磷酸化。由于ephrinB和Src在血管生成中都起关键作用，因此PS1/y分泌酶可能调节ephrinB介导的血管生成。在这里，我们发现y分泌酶以src依赖的方式促进内皮细胞对EphB的血管生成反应，y分泌酶裂解ephrinB （ephrinB/CTF2细胞质肽）的产物也是如此，其产生受EphB受体的刺激。提示PSI/y-分泌酶可能调控ephb诱导的

Alzheimer's disease (AD) is a neurodegenerative disease characterized by severe neurovascular disfunction. Increasing evidence implicates cerebral microvasculature abnormalities in the genesis of AD neuropathology. Presenilin 1 (PS1) is a protein of central importance to the neuropathology of AD. Mutations in this protein are linked to many cases of autosomal dominant forms of AD. PS1 controls the y-secretase cleavage of several type I transmembrane proteins producing cytoplasmic peptides with signaling and gene expression functions. We recently showed that PS1/y-secretase cleaves ephrinB proteins and promotes the EphB-induced phosphorylation of Src. Since both ephrinB and Src play a critical role in angiogenesis it is possible that PS1/y-secretase may regulate ephrinB-mediated angiogenesis. Here we show that y-secretase promotes the angiogenic response of endothelial cells to EphB in a Src-dependent manner and so does the product of y-secretase cleavage of ephrinB (ephrinB/CTF2 cytoplasmic peptide), whose production is stimulated by EphB receptor. This suggests that PSI/y-secretase may regulate the EphB-induced angiogenesis by cleaving ephrinB and activating Src via this cleavage. To elucidate the mechanism by which PS1/y-secretase promotes the EphB-induced Src activation we analyze the association of ephrinB/CTF2 peptide with the Src regulatory complex. This complex consists of the adaptor protein PAG/Cbp and the regulatory kinase Csk, which regulate the autophosphorylation and activation of Src. We found that ephrinB/CTF2 forms specific complexes with PAG/Cbp affecting its phosphorylation on tyrosine residues and its association with Csk kinase and that PAG/Cbp mediates the EphB-induced angiogenic response of endothelial cells in two in vitro angiogenesis assays. Our data suggest that PS1/y-secretase promotes EphBinduced angiogenesis by cleaving ephrinB, producing ephrinB/CTF2 peptide, which interacts with the Src regulatory machinery promoting Src activation and cell sprouting. Thus PS1/y-secretase may regulate development and integrity of the brain vasculature, and PS1 mutations found in Familial AD may impair it. We propose to examine the role of PSI/y-secretase in the EphB/ephrinB-mediated angiogenesis.