gamma-Secretase: a multifaceted regulator of angiogenesis

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 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.

1

Role of γ-secretase in growth factor receptor signalling. Ligand binding induces ectodomain shedding of the receptor allowing for the second intramembrane cleavage that releases the active cytoplasmic domain, which in the case of Notch translocates to the nucleus. Modified from Landman and Kim [22].

2

Components and assembly of the γ-secretase complex. (A) γ-secretase is composed of four different integral membrane proteins; presenilin, nicastrin, Aph-1 and Pen-2. Presenilin undergoes endoproteolysis into an N-terminal fragment (NTF) and C-terminal fragment (CTF) that remain associated. (B) Model for how the components of γ-secretase are arranged within the active protease complex. Modified from Wolfe [30].