PORCN-inhibitor LGK974 prevents WNT ligand palmitoyltation and secretion

Stable Identifier
R-HSA-5340560
Type
Reaction [binding]
Species
Homo sapiens
Compartment
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Porcupine (PORCN) is an O-acyl-transferase that catalyzes the palmitoleoylation of WNT ligands at the conserved S209 (van den Heuvel et al, 1993; Kadowaki et al, 1996; Hofmann, 2000). This lipid modification is required for the trafficking of WNT ligands from the ER to the cell surface, and is also required for binding to the FZD receptors. In the absence of PORCN, WNT ligand accumulates in the ER and WNT signaling is abrogated (reviewed in MacDonald et al, 2009; Takada et al, 2006; Janda et al, 2012; Herr and Basler, 2012; Ching et al, 2008). PORCN is required for activity of all human WNT ligands (Proffitt et al, 2012; Najdi et al, 2012).

LGK974 is a small molecule inhibitor of PORCN that was identified in a screen for compounds that block WNT secretion (Liu et al, 2013). LGK974 potently blocks WNT signaling in vitro and in vivo and is in Phase I clinical trials (NCT01351103) for use in the treatment of WNT-dependent cancers.

Literature References
PubMed ID Title Journal Year
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
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
24277854 Targeting Wnt-driven cancer through the inhibition of Porcupine by LGK974

Liu, J, Pan, S, Hsieh, MH, Ng, N, Sun, F, Wang, T, Kasibhatla, S, Schuller, AG, Li, AG, Cheng, D, Li, J, Tompkins, C, Pferdekamper, A, Steffy, A, Cheng, J, Kowal, C, Phung, V, Guo, G, Wang, Y, Graham, MP, Flynn, S, Brenner, JC, Li, C, Villarroel, MC, Schultz, PG, Wu, X, McNamara, P, Sellers, WR, Petruzzelli, L, Boral, AL, Seidel, HM, McLaughlin, ME, Che, J, Carey, TE, Vanasse, G, Harris, JL

Proc. Natl. Acad. Sci. U.S.A. 2013
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
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
22653731 Structural basis of Wnt recognition by Frizzled

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

Science 2012
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
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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Name Identifier Synonyms
cancer 162 malignant tumor, malignant neoplasm, primary cancer
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