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gamma-Secretase: a multifaceted regulator of angiogenesis.

Boulton ME, Cai J, Grant MB - J. Cell. Mol. Med. (2008)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Ophthalmology and Visual Sciences, University of Texas Medical Branch, Galveston, TX, USA. meboulton@ufl.edu

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.

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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].
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fig02: 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].

Mentions: γ-secretase is a complex composed of four different integral membrane proteins: presenilin (PS), nicastrin, Aph-1, and Pen-2 (Fig. 2) [29, 30]. The most studied component of the γ-secretase complex is presenilin, which is an integral enzyme in the cleavage of amyloid precursor protein and contributes to the accumulation of amyloid-β peptide in Alzheimer's disease. Activation of PS is dependent on its endoproteolysis into an N-terminal fragment (NTF) and C-terminal fragment (CTF) [30, 31]. Nicastrin has recently been described as ‘the gatekeeper of the γ-secretase complex’[32]. The extracellular orientated domain of nicastrin is essential for substrate recognition by the γ-secretase complex and nicastrin binding to the substrate is required before presenilin can exert its proteolytic activity. This extracellular domain of nicastrin usually binds to specific amino terminal residues of the transmembrane substrate. Thus nicastrin facilitates presenilin-dependent RIP of the transmembrane fragment [33]. Of the two other proteins, which constitute γ-secretase, Aph-1 is believed to be a scaffolding protein and Pen-2 appears to regulate PS activity. Assembly of the γ-secretase complex begins in the endoplasmic reticulum and is concluded after translocation of the four proteins to the cell membrane [30].


gamma-Secretase: a multifaceted regulator of angiogenesis.

Boulton ME, Cai J, Grant MB - J. Cell. Mol. Med. (2008)

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].
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4401127&req=5

fig02: 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].
Mentions: γ-secretase is a complex composed of four different integral membrane proteins: presenilin (PS), nicastrin, Aph-1, and Pen-2 (Fig. 2) [29, 30]. The most studied component of the γ-secretase complex is presenilin, which is an integral enzyme in the cleavage of amyloid precursor protein and contributes to the accumulation of amyloid-β peptide in Alzheimer's disease. Activation of PS is dependent on its endoproteolysis into an N-terminal fragment (NTF) and C-terminal fragment (CTF) [30, 31]. Nicastrin has recently been described as ‘the gatekeeper of the γ-secretase complex’[32]. The extracellular orientated domain of nicastrin is essential for substrate recognition by the γ-secretase complex and nicastrin binding to the substrate is required before presenilin can exert its proteolytic activity. This extracellular domain of nicastrin usually binds to specific amino terminal residues of the transmembrane substrate. Thus nicastrin facilitates presenilin-dependent RIP of the transmembrane fragment [33]. Of the two other proteins, which constitute γ-secretase, Aph-1 is believed to be a scaffolding protein and Pen-2 appears to regulate PS activity. Assembly of the γ-secretase complex begins in the endoplasmic reticulum and is concluded after translocation of the four proteins to the cell membrane [30].

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Ophthalmology and Visual Sciences, University of Texas Medical Branch, Galveston, TX, USA. meboulton@ufl.edu

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.

Show MeSH
Related in: MedlinePlus