Research ArticleBiochemistry

Dynamic palmitoylation controls the microdomain localization of the DKK1 receptors CKAP4 and LRP6

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Science Signaling  19 Nov 2019:
Vol. 12, Issue 608, eaat9519
DOI: 10.1126/scisignal.aat9519

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DKK1 promotes receptor depalmitoylation

Dickkopf1 (DKK1) inhibits Wnt signaling by promoting internalization of the Wnt coreceptor LRP6. DKK1 also binds to the cell surface receptor CKAP4 and stimulates signaling through the kinases PI3K and AKT, which promotes cell proliferation. Using cultured cancer cell lines, Sada et al. found that CKAP4 and LRP6 were palmitoylated and localized to lipid rafts. Palmitoylation of CKAP4 was required for DKK1-stimulated cell proliferation. DKK1 stimulated depalmitoylation of both receptors, causing them to move out of lipid rafts in a PI3K- and AKT-dependent manner, and removal of CKAP4 from lipid rafts desensitized cells to DKK1. DKK1, CKAP4, and LRP6 formed a ternary complex, and LRP6 enhanced PI3K-AKT activation downstream of DKK1 and CKAP4. Thus, dynamic palmitoylation of DKK1 receptors plays an important role in both mediating the response to DKK1 and in controlling the sensitivity of cells to DKK1.

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