gamma-Secretase: a multifaceted regulator of angiogenesis.
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 gamma-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 gamma-secretase-induced translocation of receptors to the nucleus provides an alternative intracellular signalling pathway, which acts as a potent regulator of transcription. gamma-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 gamma-secretase. This seeming complexity allows numerous possibilities for the development of targeted gamma-secretase agonists/antagonists, which can specifically regulate the angiogenic process. This review will consider the structure and function of gamma-secretase, the growing evidence for its role in angiogenesis and the substrates involved, gamma-secretase as a therapeutic target and future challenges in this area.
Boulton
Michael E
ME
Ophthalmology and Visual Sciences, University of Texas Medical Branch, Galveston, TX, USA. meboulton@ufl.edu
Cai
Jun
J
Grant
Maria B
MB
D053829:Amyloid Precursor Protein Secretases / Q000737:chemistry / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism; D002462:Cell Membrane / Q000201:enzymology / Q000378:metabolism; D010450:Endopeptidases; D066246:ErbB Receptors / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D008954:Models, Biological; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D010447:Peptide Hydrolases; D010766:Phosphorylation; D053764:Presenilin-1 / Q000378:metabolism; D053766:Presenilin-2 / Q000378:metabolism; D011485:Protein Binding; D066247:Receptor, ErbB-4; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D051880:Receptors, Notch / Q000378:metabolism; D013379:Substrate Specificity; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism
D016564:Amyloid beta-Protein Precursor; D015820:Cadherins; D008565:Membrane Proteins; D053764:Presenilin-1; D053766:Presenilin-2; D051880:Receptors, Notch; C587689:ERBB4 protein, human; D066246:ErbB Receptors; D066247:Receptor, ErbB-4; D017526:Receptor, IGF Type 1; D040281:Vascular Endothelial Growth Factor Receptor-1; C475154:APH1A protein, human; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D010447:Peptide Hydrolases