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The molecular function of NOTUM has remained unclear for many years. It was initially thought to hydrolyze glycosaminoglycan (GAG) chains of glypicans, thereby affecting glypicans ability to interact with Wnt ligands. It was later reported to trigger glypican shedding, by mediating cleavage of their GPI-anchor. However, while NOTUM specifically inhibit the Wnt signaling pathway, more pleiotropic effects would be expected from an enzyme affecting glypicans. It was finally shown that it requires glypicans to suppress Wnt signaling, but does not cleave their GPI-anchor. It acts by mediating depalmitoleoylation of WNT proteins, impairing WNT binding to frizzled receptors.

Notum

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