Signaling Differentiation

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Sci. Signal.  22 Jan 2013:
Vol. 6, Issue 259, pp. ec19
DOI: 10.1126/scisignal.2003977

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. 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. The GDPD activity of GDE2 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.

S. Park, C. Lee, P. Sabharwal, M. Zhang, C. L. Freel Meyers, S. Sockanathan, GDE2 promotes neurogenesis by glycosylphoshatidylinositol-anchor cleavage of RECK. Science 339, 324–328 (2013). [Abstract] [Full Text]