gamma-Secretase: a multifaceted regulator of angiogenesis.
gamma-Secretase: a multifaceted regulator of angiogenesis.
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DOI：
10.1111/j.1582-4934.2008.00274.x
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发表时间：
2008-06
影响因子：
5.3
通讯作者：
Grant MB
中科院分区：
文献类型：
--
作者：
Boulton ME;Cai J;Grant MB
生理性血管生成对发育、体内平衡和组织修复至关重要，但病理性新生血管形成是肿瘤、类风湿关节炎和眼部并发症的主要特征。过去十年的研究已经确定γ-分泌酶是一种依赖于早老素的蛋白酶，通过以下途径作为血管生成的关键调节因子：(i)调节膜内蛋白水解和受体的跨膜切割（如VEGFR-1、Notch、ErbB-4、IGFI-R），随后将细胞内结构域易位至细胞核，（ii）全长膜结合受体易位至细胞核（VEGFR-1）， （iii）膜结合蛋白磷酸化（VEGFR-1和ErbB-4），（iv）粘附体连接（钙粘蛋白）的调节和通透性的调节；(v)淀粉样蛋白前体蛋白裂解成淀粉样蛋白-β，它能够调节血管生成过程。γ-分泌酶诱导的受体向细胞核的易位提供了另一种细胞内信号通路，它作为转录的有效调节剂。γ-分泌酶是由四种不同的完整蛋白（早老素、nicastrin、Aph-1和Pen-2）组成的复合物，它们决定了γ-分泌酶的稳定性、底物结合性、底物特异性和蛋白水解活性。这种表面上的复杂性为开发靶向γ-分泌酶激动剂/拮抗剂提供了许多可能性，它们可以特异性地调节血管生成过程。本文将对γ-分泌酶的结构和功能、越来越多的证据表明γ-分泌酶在血管生成中的作用及其所涉及的底物、γ-分泌酶作为治疗靶点以及该领域未来的挑战进行综述。
Physiological angiogenesis is essential for development, homeostasis and tissue repair but pathological neovascularization is a major feature of tumours, rheumatoid arthritis and ocular complications. Studies over the last decade have identified γ-secretase, a presenilin-dependent protease, as a key regulator of angiogenesis through: (i) regulated intramembrane proteolysis and transmembrane cleavage of receptors (e.g. VEGFR-1, Notch, ErbB-4, IGFI-R) followed by translocation of the intracellular domain to the nucleus, (ii) translocation of full length membrane-bound receptors to the nucleus (VEGFR-1), (iii) phosphorylation of membrane bound proteins (VEGFR-1 and ErbB-4), (iv) modulation of adherens junctions (cadherin) and regulation of permeability and (v) cleavage of amyloid precursor protein to amyloid-β which is able to regulate the angiogenic process. The γ-secretase-induced translocation of receptors to the nucleus provides an alternative intracellular signalling pathway, which acts as a potent regulator of transcription. γ-secretase is a complex composed of four different integral proteins (presenilin, nicastrin, Aph-1 and Pen-2), which determine the stability, substrate binding, substrate specificity and proteolytic activity of γ-secretase. This seeming complexity allows numerous possibilities for the development of targeted γ-secretase agonists/antagonists, which can specifically regulate the angiogenic process. This review will consider the structure and function of γ-secretase, the growing evidence for its role in angiogenesis and the substrates involved, γ-secretase as a therapeutic target and future challenges in this area.
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影响因子：
4.8
作者：
Cai, J;Jiang, WG;Boulton, M
通讯作者：
Boulton, M
影响因子：
44.1
作者：
Blazquez, C;Cook, N;Pezzella, F
通讯作者：
Pezzella, F
影响因子：
11.2
作者：
Amin, DN;Hida, K;Klagsbrun, M
通讯作者：
Klagsbrun, M
影响因子：
11.4
作者：
Georgakopoulos, A;Litterst, C;Robakis, NK
通讯作者：
Robakis, NK
影响因子：
11.4
作者：
Baki, L;Shioi, J;Robakis, NK
通讯作者：
Robakis, NK