PORCN palmitoleoylates N-glycosyl WNTs

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R-HSA-3238694
Type
Reaction [transition]
Species
Homo sapiens
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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
17141155 Monounsaturated fatty acid modification of Wnt protein: its role in Wnt secretion

Takada, R, Satomi, Y, Kurata, T, Ueno, N, Norioka, S, Kondoh, H, Takao, T, Takada, S

Dev. Cell 2006
21554866 Porcupine homolog is required for canonical Wnt signaling and gastrulation in mouse embryos

Biechele, S, Cox, BJ, Rossant, J

Dev. Biol. 2011
8262072 Mutations in the segment polarity genes wingless and porcupine impair secretion of the wingless protein

van den Heuvel, M, Harryman-Samos, C, Klingensmith, J, Perrimon, N, Nusse, R

EMBO J. 1993
22653731 Structural basis of Wnt recognition by Frizzled

Janda, CY, Waghray, D, Levin, AM, Thomas, C, Garcia, KC

Science 2012
12717451 Wnt proteins are lipid-modified and can act as stem cell growth factors

Willert, K, Brown, JD, Danenberg, E, Duncan, AW, Weissman, IL, Reya, T, Yates, JR, Nusse, R

Nature 2003
8985181 The segment polarity gene porcupine encodes a putative multitransmembrane protein involved in Wingless processing

Kadowaki, T, Wilder, E, Klingensmith, J, Zachary, K, Perrimon, N

Genes Dev. 1996
17397399 Glycosylation and palmitoylation of Wnt-3a are coupled to produce an active form of Wnt-3a

Komekado, H, Yamamoto, H, Chiba, T, Kikuchi, A

Genes Cells 2007
22046319 Differential palmit(e)oylation of Wnt1 on C93 and S224 residues has overlapping and distinct consequences

Galli, LM, Burrus, LW

PLoS ONE 2011
22108505 Porcupine-mediated lipidation is required for Wnt recognition by Wls

Herr, P, Basler, K

Dev. Biol. 2012
22784633 A uniform human Wnt expression library reveals a shared secretory pathway and unique signaling activities

Najdi, R, Proffitt, K, Sprowl, S, Kaur, S, Yu, J, Covey, TM, Virshup, DM, Waterman, ML

Differentiation 2012
10694878 A superfamily of membrane-bound O-acyltransferases with implications for wnt signaling

Hofmann, K

Trends Biochem. Sci. 2000
22888000 Precise regulation of porcupine activity is required for physiological Wnt signaling

Proffitt, KD, Virshup, DM

J. Biol. Chem. 2012
21768372 Deletion of mouse Porcn blocks Wnt ligand secretion and reveals an ectodermal etiology of human focal dermal hypoplasia/Goltz syndrome

Barrott, JJ, Cash, GM, Smith, AP, Barrow, JR, Murtaugh, LC

Proc. Natl. Acad. Sci. U.S.A. 2011
19619488 Wnt/beta-catenin signaling: components, mechanisms, and diseases

MacDonald, BT, Tamai, K, He, X

Dev Cell 2009
18430724 Lipid-independent secretion of a Drosophila Wnt protein

Ching, W, Hang, HC, Nusse, R

J. Biol. Chem. 2008
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Title
O-acyltransferase activity of PORCN [endoplasmic reticulum membrane]
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