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Cited by 118Developmental Biology and Gene RegulationNeurogenesis and neuroplasticity mechanismsProtein Kinase Regulation and GTPase Signaling

GDE2 Promotes Neurogenesis by Glycosylphosphatidylinositol-Anchor Cleavage of RECK

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Park, Sungjin, Lee, Changhee, Sabharwal, Priyanka, Zhang, Mei, Meyers, Caren L. Freel, Sockanathan, Shanthini·2013·Science
DOI 10.1126/science.1231921PMC PMC3644959
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Abstract

Signaling Differentiation: The six-transmembrane protein GDE2 promotes differentiation through extracellular glycerophosphodiester phosphodiesterase (GDPD) activity and induces neuronal differentiation through inhibition of Notch signaling—a major pathway that maintains stem or progenitor cell states and is implicated in multiple cancers. How then, does GDPD activity inhibit Notch signaling, given that GDPD enzymes are known to metabolize glycerophosphodiesters into glycerol-3-phosphate and corresponding alcohols? Park et al. (p. 324 ) show that the six-transmembrane GDPDs such as GDE2, do not function as conventional GDPD enzymes, but instead cleave the glycosylphosphatidylinositol (GPI) anchors of GPI-anchored proteins. GDE2 GDPD activity cleaves and inactivates the GPI-anchored protein RECK, which normally acts to prevent shedding of the Notch ligand Delta. Accordingly, RECK inactivation stimulates Delta shedding leading to Notch inactivation in progenitors and the initiation of cellular differentiation.

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  • GDE2 is one of three known GPI-anchor cleaving enzymes in vertebrates and the only one expressed in neurons.

    “GDE2 is one of three known GPI-anchor cleaving enzymes in vertebrates that function at the cell surface, and the only one expressed in neurons (22–26).”

    From GDE2-RECK controls ADAM10 α-secretase–mediated cleavage of amyloid precursor protein (2021) · cites this paper as [26]

    The paper reports GDE2-mediated GPI-anchor cleavage at the cell surface and names two previously identified vertebrate GPI-anchor-cleaving enzymes (Abstract; page unavailable). It does not establish that exactly three such enzymes function at the cell surface or that GDE2 is the only one expressed in neurons; it also describes GDE3 and GDE6 as sharing cleavage activity. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • GDE2 is the only known GPI-anchor cleaving enzyme in vertebrates that functions at the cell surface in neurons to release GPI-anchored proteins into the extracellular space.

    “GDE2 is the only known GPI-anchor cleaving enzyme in vertebrates that functions at the cell surface in neurons to release GPI-anchored proteins into the extracellular space (26)”

    From GDE2-RECK controls ADAM10 α-secretase–mediated cleavage of amyloid precursor protein (2021) · cites this paper as [26]

    The paper reports that GDE2 releases GPI-anchored RECK from the cell surface into the medium and links this activity to spinal motor neuron differentiation (Abstract; Fig. 3F). It does not establish that GDE2 is the only vertebrate enzyme with this function in neurons; it also describes GPI-anchor cleavage as an activity shared by GDE3 and GDE6. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • In the developing nervous system, ADAM10 activity is regulated by the GDE2-RECK pathway.

    “In the developing nervous system, ADAM10 activity is regulated by the GDE2-RECK pathway.”

    From GDE2-RECK controls ADAM10 α-secretase–mediated cleavage of amyloid precursor protein (2021) · cites this paper as [26]

  • During embryonic neurogenesis, GDE2 promotes ADAM10 activity by cleaving RECK at the GPI-anchor and removing RECK from neuronal surfaces.

    “During embryonic neurogenesis, GDE2 promotes ADAM10 activity by cleaving RECK at the GPI-anchor and removing RECK from neuronal surfaces (26).”

    From GDE2-RECK controls ADAM10 α-secretase–mediated cleavage of amyloid precursor protein (2021) · cites this paper as [26]

  • RECK inactivation leads to ADAM10 shedding of Dll1, downregulation of Notch signaling in adjacent progenitors and induction of neuronal differentiation.

    “RECK inactivation leads to ADAM10 shedding of the Notch ligand Delta-like 1 (Dll1), downregulation of Notch signaling in adjacent progenitors and induction of neuronal differentiation (Figure S1A) (26).”

    From GDE2-RECK controls ADAM10 α-secretase–mediated cleavage of amyloid precursor protein (2021) · cites this paper as [26]

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Cites

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Research works printed but not linked: 26

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Authors
Park, S., Lee, C., Sabharwal, P., Zhang, M., Meyers, C. L. F., & Sockanathan, S.
Affiliations
  • Solomon Snyder Department of Neuroscience, School of Medicine, Johns Hopkins University, PCTB1004, 725 N Wolfe Street, Baltimore, MD 21205, USA.
  • Johns Hopkins University (US)
Corresponding author
  • Lee, Changhee
  • Sockanathan, Shanthini
ORCID
Venue
Science
Publisher
American Association for the Advancement of Science (AAAS)
Published
2013-01-18
Volume
339
Issue
6117
Pages
324-328
ISSN
  • 0036-8075 (ISSN-L)
  • 1095-9203
DOI
10.1126/science.1231921
PMC
PMC3644959
OpenAlex
W1971218315
Cited by
118
References
2
Citations by year
2026: 4 · 2025: 6 · 2024: 16 · 2023: 4 · 2022: 9 · 2021: 9 · 2020: 17 · 2019: 8 · 2018: 5 · 2017: 11 · 2016: 11 · 2015: 9 · 2014: 5 · 2013: 4
FWCI
4.33
Type
journal article
Language
en
Open access
Locations
  • Science (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Institute of Neurological Disorders and Stroke (R01NS046336)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Keywords
glycerophosphodiester phosphodiesterase, RECK, Notch signaling inhibition, DLL1, ADAM proteases, proteolytic shedding, motor neuron progenitors, neurogenesis, GPI-anchored proteins
MeSH terms
Animals, Chick Embryo, Motor Neurons, Phosphoric Diester Hydrolases, Spinal Cord, Glycosylphosphatidylinositols, RNA, Small Interfering, Intercellular Signaling Peptides and Proteins, ADAM Proteins, Receptors, Notch, Neurogenesis, GPI-Linked Proteins

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