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Characterization at the Molecular Level using Robust Biochemical Approaches of a New Kinase Protein
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Characterization at the Molecular Level using Robust Biochemical Approaches of a New Kinase Protein

Published on: June 30, 2019

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

Ryota Sada1, Hirokazu Kimura1, Yuko Fukata2,3

  • 1Department of Molecular Biology and Biochemistry, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita 565-0871, Japan.

Science Signaling
|November 21, 2019
PubMed

Insights

Dickkopf1 (DKK1) signaling in cancer relies on palmitoylation of CKAP4 and LRP6. DKK1 triggers depalmitoylation, promoting cancer cell proliferation via PI3K-AKT activation.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Cancer Research

Background:

  • Dickkopf1 (DKK1) antagonizes Wnt signaling by targeting LRP5/6 for endocytosis.
  • Cytoskeleton-associated protein 4 (CKAP4) acts as a plasma membrane receptor and is implicated in cancer progression.
  • The DKK1-CKAP4 pathway activates PI3K/AKT signaling, promoting cancer cell proliferation.

Purpose of the Study:

  • To investigate the role of protein palmitoylation in the DKK1-CKAP4 signaling pathway.
  • To elucidate the mechanism by which DKK1 regulates CKAP4 and LRP6 localization and function.
  • To understand the interplay between LRP5/6 and CKAP4 in DKK1-mediated cancer cell proliferation.

Main Methods:

  • Analysis of protein localization in detergent-resistant membrane (DRM) and non-DRM fractions.
  • Assessment of protein palmitoylation and depalmitoylation using acylprotein thioesterases (APTs).
  • Knockdown studies of LRP5/6 and CKAP4 to evaluate their roles in signaling and proliferation.

Main Results:

  • CKAP4 and LRP6 are palmitoylated and localized to DRMs, with CKAP4 palmitoylation essential for proliferation.
  • DKK1 induces depalmitoylation of CKAP4 and LRP6 via APTs, leading to their translocation to non-DRMs.
  • DKK1-induced depalmitoylation requires PI3K-AKT pathway activation, and LRP5/6 enhances DKK1-CKAP4 signaling.

Conclusions:

  • Protein palmitoylation state is critical for CKAP4 and LRP6 signaling in cancer.
  • DKK1 modulates CKAP4 and LRP6 function through regulated depalmitoylation.
  • LRP5/6 receptors potentiate DKK1-CKAP4 signaling, highlighting a novel therapeutic target in cancer.

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