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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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Related in: MedlinePlus

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].
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fig01: 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].

Mentions: Over the last decade regulated intramembrane proteolysis (RIP) has been revealed as a novel, but highly conserved mechanism in cell signalling (reviewed in [20–22]). RIP results in the release of extracellular/luminal and/or cytoplasmic domains from transmembrane proteins. These cleaved fragments have been shown to act as biological effectors at other sites within the cell. For example, the intracellular domain of Notch released by RIP translocates to the nucleus where it acts as a transcriptional activator [23] (Fig. 1). RIP is mediated by at least three distinct families of evolutionarily conserved intramembrane proteases, which cleave substrates usually within their transmembrane domains [22]:(1) the presenilin-type aspartyl proteases, including the presenilin-dependent γ-secretase and the signal peptide peptidase (SPP) that cleave tyrosine kinase receptors and the HLA-E epitope [24–25]; (2) the site-2 protease (S2P) family, zinc-metalloproteases that cleave and activate sterol regulatory element binding proteins (SREBPs) [26]; (3) the rhomboid serine proteases that cleave transmembrane ligand substrates including the main EGF ligand Spitz [27]. Presenilin-dependent γ-secretase and rhomboids are believed to cleave only type-I membrane substrates (single pass transmembrane proteins with a cytoplasmic C-terminus and an extracellular or luminal N-terminus), while S2P and SPP cleave type-II membrane proteins (the N- and C-termini in type II proteins are the reverse orientation of type-I proteins). Cleavage of multipass proteins is under debate but there is recent evidence that this might occur with the CXCR4 receptor [28].


gamma-Secretase: a multifaceted regulator of angiogenesis.

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

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].
© Copyright Policy
Related In: Results  -  Collection

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

fig01: 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].
Mentions: Over the last decade regulated intramembrane proteolysis (RIP) has been revealed as a novel, but highly conserved mechanism in cell signalling (reviewed in [20–22]). RIP results in the release of extracellular/luminal and/or cytoplasmic domains from transmembrane proteins. These cleaved fragments have been shown to act as biological effectors at other sites within the cell. For example, the intracellular domain of Notch released by RIP translocates to the nucleus where it acts as a transcriptional activator [23] (Fig. 1). RIP is mediated by at least three distinct families of evolutionarily conserved intramembrane proteases, which cleave substrates usually within their transmembrane domains [22]:(1) the presenilin-type aspartyl proteases, including the presenilin-dependent γ-secretase and the signal peptide peptidase (SPP) that cleave tyrosine kinase receptors and the HLA-E epitope [24–25]; (2) the site-2 protease (S2P) family, zinc-metalloproteases that cleave and activate sterol regulatory element binding proteins (SREBPs) [26]; (3) the rhomboid serine proteases that cleave transmembrane ligand substrates including the main EGF ligand Spitz [27]. Presenilin-dependent γ-secretase and rhomboids are believed to cleave only type-I membrane substrates (single pass transmembrane proteins with a cytoplasmic C-terminus and an extracellular or luminal N-terminus), while S2P and SPP cleave type-II membrane proteins (the N- and C-termini in type II proteins are the reverse orientation of type-I proteins). Cleavage of multipass proteins is under debate but there is recent evidence that this might occur with the CXCR4 receptor [28].

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