Reactome: A Curated Pathway Database

PORCN palmitoleoylates N-glycosyl WNTs

Stable Identifier
Homo sapiens
Locations in the PathwayBrowser

All WNT proteins except Drosophila WntD are lipid modified. Lipid modifications contribute to the hydrophobicity and poor solubility of all known WNT ligands with the exception of Drosophila WntD. Acylation is required for their secretion from the cell and their ability to bind to FRZ receptors (reviewed in MacDonald et al, 2009; Takada et al, 2006; Janda et al, 2012; Herr and Basler, 2012; Ching et al, 2008). Although an initial study suggested that conserved Cys77 in mouse Wnt3a was palmitoylated (Willert et al, 2003), further work showed that mutation of this residue had minimal effect on WNT secretion (Komekado et al, 2007). In contrast, addition of palmitoleic acid to mWnt3a Ser209 is essential for WNT secretion, and mutant S209A is largely retained in the ER (Takada et al, 2006; Galli and Burrus, 2011). This serine residue is conserved at this position in all known WNTs with the exception of Drosophila WntD (Ching et al, 2008; Herr and Basler, 2012). A recent crystal structure of Xenopus WNT8 in complex with a Frizzled cysteine-rich-domain shows a single lipid modification on the conserved serine residue, while the conserved cysteine participates in a disulphide bond (Janda et al, 2012). In addition to being required for secretion, the lipid at S209 also makes direct contact with a groove in the Frizzled receptor and is thus essential for binding (Janda et al, 2012).

Porcupine is a conserved multi-pass transmembrane ER protein that has an O-acyl-transferase domain (van den Heuvel et al, 1993; Kadowaki et al, 1996; Hofmann, 2000). First identified in Drosophila, Porcupine is a WNT-specific modulator that is required for Wingless processing and secretion (Kadowaki et al, 1996). In porcn-deficient cells, Wg and WNT3A have decreased palmitoylation at S209 and accumulate in the ER (Takada et al, 2006), and mutations in PORCN eliminate all WNT signalling and cause embryonic lethality in mice (Barrott et al, 2011; Biechele et al, 2011). Recent studies show that PORCN is required for activity of all human WNT ligands (Proffitt et al, 2012; Najdi et al, 2012).

Literature References
PubMed ID Title Journal Year
10694878 A superfamily of membrane-bound O-acyltransferases with implications for wnt signaling Trends Biochem. Sci. 2000
22784633 A uniform human Wnt expression library reveals a shared secretory pathway and unique signaling activities Differentiation 2012
21768372 Deletion of mouse Porcn blocks Wnt ligand secretion and reveals an ectodermal etiology of human focal dermal hypoplasia/Goltz syndrome Proc. Natl. Acad. Sci. U.S.A. 2011
22046319 Differential palmit(e)oylation of Wnt1 on C93 and S224 residues has overlapping and distinct consequences PLoS ONE 2011
17397399 Glycosylation and palmitoylation of Wnt-3a are coupled to produce an active form of Wnt-3a Genes Cells 2007
18430724 Lipid-independent secretion of a Drosophila Wnt protein J. Biol. Chem. 2008
17141155 Monounsaturated fatty acid modification of Wnt protein: its role in Wnt secretion Dev. Cell 2006
8262072 Mutations in the segment polarity genes wingless and porcupine impair secretion of the wingless protein EMBO J. 1993
21554866 Porcupine homolog is required for canonical Wnt signaling and gastrulation in mouse embryos Dev. Biol. 2011
22108505 Porcupine-mediated lipidation is required for Wnt recognition by Wls Dev. Biol. 2012
22888000 Precise regulation of porcupine activity is required for physiological Wnt signaling J. Biol. Chem. 2012
22653731 Structural basis of Wnt recognition by Frizzled Science 2012
8985181 The segment polarity gene porcupine encodes a putative multitransmembrane protein involved in Wingless processing Genes Dev. 1996
12717451 Wnt proteins are lipid-modified and can act as stem cell growth factors Nature 2003
19619488 Wnt/beta-catenin signaling: components, mechanisms, and diseases Dev Cell 2009
Participant Of
This entity is regulated by:
Title Physical Entity Activity
O-acyltransferase activity of PORCN [endoplasmic reticulum membrane] PORCN [endoplasmic reticulum membrane] O-acyltransferase activity (0008374)
Inferred From