?-Secretase: a multifaceted regulator of angiogenesis #MMPMID18266961
Boulton ME; Cai J; Grant MB
J Cell Mol Med 2008[Jun]; 12 (3): 781-95 PMID18266961show ga
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 ?-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-? which is able to regulate the angiogenic process. The ?-secretase-induced translocation of receptors to the nucleus provides an alternative intracellular signalling pathway, which acts as a potent regulator of transcription. ?-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 ?-secretase. This seeming complexity allows numerous possibilities for the development of targeted ?-secretase agonists/antagonists, which can specifically regulate the angiogenic process. This review will consider the structure and function of ?-secretase, the growing evidence for its role in angiogenesis and the substrates involved, ?-secretase as a therapeutic target and future challenges in this area.
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J+Cell+Mol+Med 2008 ; 12 (3): 781-95
