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.

Abstract

Dickkopf1 (DKK1) was originally identified as an antagonist of Wnt signaling that binds to and induces the clathrin-mediated endocytosis of the Wnt coreceptors low-density lipoprotein receptor–related proteins 5 and 6 (LRP5/6). DKK1 also binds to cytoskeleton-associated protein 4 (CKAP4), which was originally identified as an endoplasmic reticulum (ER) protein but also functions at the plasma membrane as a receptor for various ligands. The DKK1-CKAP4 pathway is activated in several human cancers and promotes cell proliferation by activating signaling through the kinases PI3K and AKT. We found that both CKAP4 and LRP6 primarily localized to detergent-resistant membrane (DRM) fractions of the plasma membrane in a palmitoylation-dependent manner and that palmitoylation of CKAP4 was required for it to promote cell proliferation. DKK1 induced the depalmitoylation of both CKAP4 and LRP6 by acylprotein thioesterases (APTs), resulting in their translocation to the non-DRM fractions. Moreover, DKK1-dependent depalmitoylation of both receptors required activation of the PI3K-AKT pathway. DKK1 simultaneously bound CKAP4 and LRP6, resulting in the formation of a ternary complex. LRP5/6 knockdown decreased DKK1-dependent AKT activation and cancer cell proliferation through CKAP4, whereas CKAP4 knockdown did not affect DKK1-dependent inhibition of Wnt signaling through LRP5/6. These results indicate that the palmitoylation states of CKAP4 and LRP6 play important roles in their signaling and that LRP5/6 enhance DKK1-CKAP4 signaling.

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