Stearoyl CoA desaturase is required to produce active, lipid-modified Wnt proteins

By Jessica Rios-Esteves, M. Resh. 2013

147 citations recorded by the source corpus.

Summary Wnt proteins contain an unusual lipid modification, palmitoleic acid. Production of an active Wnt signal requires the acyltransferase Porcupine and depends on attachment of palmitoleic acid to Wnt. The source of this monounsaturated fatty acid has not been identified, and it is not known how Porcupine recognizes its substrate and whether desaturation occurs before or after fatty acid transfer to Wnt. Here we show that stearoyl desaturase (SCD) generates a monounsaturated fatty acid substrate which is then transferred by Porcupine to Wnt. Treatment of cells with SCD inhibitors blocked incorporation of palmitate analogs into Wnt3a and Wnt5a, and reduced Wnt secretion as well as autocrine and paracrine Wnt signaling. The SCD inhibitor effects were rescued by exogenous addition of monounsaturated fatty acids. We propose that SCD is a key molecular player responsible for Wnt biogenesis and processing and that SCD inhibition provides an alternative mechanism for blocking Wnt pathway activation.

Subfields: Biochemistry, Molecular Biology

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Citations in the corpus

An in vitro fatty acylation assay reveals a mechanism for Wnt recognition by the acyltransferase Porcupine (2017, background): “Stearoyl-CoA desaturase first converts palmitoyl-CoA into palmitoleoyl-CoA, which is then utilized as a substrate by the Wnt acyltransferase Porcupine (PORCN)(2) (7).”
Wnt/ b -Catenin Signaling, Disease, and Emerging Therapeutic Modalities (2017, background): “Thismodification is likely shared between all Wnts and is brought about by a special palmitoyl transferase: Porcupine (Rios-Esteves and Resh, 2013).”
Structural model of PORCN illuminates disease-associated variants and drug binding sites (2021, unknown): “(Asciolla et al., 2017; Chang et al., 2010; Rios-Esteves and Resh, 2013; Tuladhar et al., 2019).”
Wnt addiction of genetically defined cancers reversed by PORCN inhibition (2015, unknown): “18,19 20-22 Inhibition of PORCN enzymatic activity offers an approach to overcome the limitations of β -catenin inhibitors that can only block the canonical Wnt signaling pathway 23-26 or the anti-Frizzled antibodies that are limited in their ability to target all the Frizzled receptors.”
Notum is required for neural and head induction via Wnt deacylation, oxidation and inactivation (2015, unknown): “See also Figure S2. metabolic labeling of Wnt3a with a palmitic acid analog (az-15) (Zhang et al., 2012), which can be desaturated and incorporated into Wnt3a in the cell (Hannoush, 2012; Rios-Esteves and Resh, 2013; Zhang et al., 2012).”
Stereoselective fatty acylation is essential for the release of lipidated WNT proteins from the acyltransferase Porcupine (PORCN) (2019, background): “An SCD inhibitor (A939572) blunted WNT acylation with a saturated fatty acyl probe (C16:0), consistent with previous observations (20), but not with the cis or trans unsaturated fatty acid probes, suggesting that the trans fat labeling was not enabled by cellular isomerization (Fig.”