Abstract
The six-transmembrane protein glycerophosphodiester phosphodiesterase 2 (GDE2) induces spinal motor neuron differentiation by inhibiting Notch signaling in adjacent motor neuron progenitors. GDE2 function requires activity of its extracellular domain that shares homology with glycerophosphodiester phosphodiesterases (GDPDs). GDPDs metabolize glycerophosphodiesters into glycerol-3-phosphate and corresponding alcohols, but whether GDE2 inhibits Notch signaling by this mechanism is unclear. Here, we show that GDE2, unlike classical GDPDs, cleaves glycosylphosphatidylinositol (GPI) anchors. GDE2 GDPD activity inactivates the Notch activator RECK (reversion-inducing cysteine-rich protein with kazal motifs) by releasing it from the membrane through GPI-anchor cleavage. RECK release disinhibits ADAM (a disintegrin and metalloproteinase) protease-dependent shedding of the Notch ligand Delta-like 1 (Dll1), leading to Notch inactivation. This study identifies a previously unrecognized mechanism to initiate neurogenesis that involves GDE2-mediated surface cleavage of GPI-anchored targets to inhibit Dll1-Notch signaling.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 324-328 |
| Number of pages | 5 |
| Journal | Science |
| Volume | 339 |
| Issue number | 6117 |
| DOIs | |
| State | Published - Jan 18 2013 |
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GDE2 promotes neurogenesis by glycosylphosphatidylinositol-anchor cleavage of RECK. / Park, Sungjin; Lee, Changhee; Sabharwal, Priyanka; Zhang, Mei; Meyers, Caren L; Sockanathan, Shanthini.
In: Science, Vol. 339, No. 6117, 18.01.2013, p. 324-328.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - GDE2 promotes neurogenesis by glycosylphosphatidylinositol-anchor cleavage of RECK
AU - Park, Sungjin
AU - Lee, Changhee
AU - Sabharwal, Priyanka
AU - Zhang, Mei
AU - Meyers, Caren L
AU - Sockanathan, Shanthini
PY - 2013/1/18
Y1 - 2013/1/18
N2 - The six-transmembrane protein glycerophosphodiester phosphodiesterase 2 (GDE2) induces spinal motor neuron differentiation by inhibiting Notch signaling in adjacent motor neuron progenitors. GDE2 function requires activity of its extracellular domain that shares homology with glycerophosphodiester phosphodiesterases (GDPDs). GDPDs metabolize glycerophosphodiesters into glycerol-3-phosphate and corresponding alcohols, but whether GDE2 inhibits Notch signaling by this mechanism is unclear. Here, we show that GDE2, unlike classical GDPDs, cleaves glycosylphosphatidylinositol (GPI) anchors. GDE2 GDPD activity inactivates the Notch activator RECK (reversion-inducing cysteine-rich protein with kazal motifs) by releasing it from the membrane through GPI-anchor cleavage. RECK release disinhibits ADAM (a disintegrin and metalloproteinase) protease-dependent shedding of the Notch ligand Delta-like 1 (Dll1), leading to Notch inactivation. This study identifies a previously unrecognized mechanism to initiate neurogenesis that involves GDE2-mediated surface cleavage of GPI-anchored targets to inhibit Dll1-Notch signaling.
AB - The six-transmembrane protein glycerophosphodiester phosphodiesterase 2 (GDE2) induces spinal motor neuron differentiation by inhibiting Notch signaling in adjacent motor neuron progenitors. GDE2 function requires activity of its extracellular domain that shares homology with glycerophosphodiester phosphodiesterases (GDPDs). GDPDs metabolize glycerophosphodiesters into glycerol-3-phosphate and corresponding alcohols, but whether GDE2 inhibits Notch signaling by this mechanism is unclear. Here, we show that GDE2, unlike classical GDPDs, cleaves glycosylphosphatidylinositol (GPI) anchors. GDE2 GDPD activity inactivates the Notch activator RECK (reversion-inducing cysteine-rich protein with kazal motifs) by releasing it from the membrane through GPI-anchor cleavage. RECK release disinhibits ADAM (a disintegrin and metalloproteinase) protease-dependent shedding of the Notch ligand Delta-like 1 (Dll1), leading to Notch inactivation. This study identifies a previously unrecognized mechanism to initiate neurogenesis that involves GDE2-mediated surface cleavage of GPI-anchored targets to inhibit Dll1-Notch signaling.
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U2 - 10.1126/science.1231921
DO - 10.1126/science.1231921
M3 - Article
VL - 339
SP - 324
EP - 328
JO - Science
JF - Science
SN - 0036-8075
IS - 6117
ER -