Open Accessγ‐Secretase: a multifaceted regulator of angiogenesis
Author(s) -
Boulton Michael E.,
Cai Jun,
Grant Maria B.
Publication year - 2008
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/j.1582-4934.2008.00274.x
Subject(s) - microbiology and biotechnology , presenilin , nicastrin , amyloid precursor protein secretase , angiogenesis , biology , lrp1 , notch signaling pathway , furin , chemistry , amyloid precursor protein , signal transduction , cancer research , biochemistry , ldl receptor , medicine , disease , alzheimer's disease , lipoprotein , cholesterol , enzyme
• Introduction • Regulated intramembrane proteolysis • γ‐Secretase – Structure – Receptor cleavage• Is there more to γ‐Secretase than regulated intramembrane proteolysis? – Receptor translocation – Presenilin‐binding proteins – Phosphorylation• Role of γ‐Secretase in angiogenesis – Notch – Vascular endothelial growth factor receptor‐1 (VEGFR‐1) – Insulin‐like growth factor‐I receptor (IGF‐1R) – ErbB4 – Cadherins – Amyloid precursor protein (APP) – Other substrates• γ‐Secretase as a therapeutic target • γ‐Secretase, what next?Abstract 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.