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CKAP4 is a Dickkopf1 receptor and is involved in tumor progression
Hirokazu Kimura, … , Eiichi Morii, Akira Kikuchi
Hirokazu Kimura, … , Eiichi Morii, Akira Kikuchi
Published June 20, 2016
Citation Information: J Clin Invest. 2016;126(7):2689-2705. https://doi.org/10.1172/JCI84658.
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Research Article Cell biology Oncology Article has an altmetric score of 14

CKAP4 is a Dickkopf1 receptor and is involved in tumor progression

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Abstract

Dickkopf1 (DKK1) is a secretory protein that antagonizes oncogenic Wnt signaling by binding to the Wnt coreceptor low-density lipoprotein receptor–related protein 6 (LRP6). DKK1 may also regulate its own signaling to promote cancer cell proliferation, but the mechanism is not understood. Here, we identified cytoskeleton-associated protein 4 (CKAP4) as a DKK1 receptor and evaluated CKAP4-mediated DKK1 signaling in cancer cell proliferation. We determined that DKK1 binds CKAP4 and LRP6 with similar affinity but interacts with these 2 receptors with different cysteine-rich domains. DKK1 induced internalization of CKAP4 in a clathrin-dependent manner, further supporting CKAP4 as a receptor for DKK1. DKK1/CKAP4 signaling activated AKT by forming a complex between the proline-rich domain of CKAP4 and the Src homology 3 domain of PI3K, resulting in proliferation of normal cells and cancer cells. Expression of DKK1 and CKAP4 was frequent in tumor lesions of human pancreatic and lung cancers, and simultaneous expression of both proteins in patient tumors was negatively correlated with prognosis and relapse-free survival. An anti-CKAP4 antibody blocked the binding of DKK1 to CKAP4, suppressed AKT activity in a human cancer cell line, and attenuated xenograft tumor formation in immunodeficient mice. Together, our results suggest that CKAP4 is a potential therapeutic target for cancers that express both DKK1 and CKAP4.

Authors

Hirokazu Kimura, Katsumi Fumoto, Kensaku Shojima, Satoshi Nojima, Yoshihito Osugi, Hideo Tomihara, Hidetoshi Eguchi, Yasushi Shintani, Hiroko Endo, Masahiro Inoue, Yuichiro Doki, Meinoshin Okumura, Eiichi Morii, Akira Kikuchi

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Figure 4

CKAP4 forms a complex with PI3K.

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CKAP4 forms a complex with PI3K.
(A) Lysates (Input) of control MDCK, MD...
(A) Lysates (Input) of control MDCK, MDCK/DKK1-FLAG, control X293T, or X293T/DKK1-FLAG cells were immunoprecipitated with anti-CKAP4 antibody or nonimmune IgG and probed with the indicated antibodies. (B) Lysates (Input) of control MDCK, MDCK/DKK1-FLAG, control X293T, or X293T/DKK1-FLAG cells were immunoprecipitated with anti-CKAP4 antibody or nonimmune IgG and probed with the indicated antibodies. (C) P85α was expressed with CKAP4-HA or CKAP4-ECD-HA in X293T/DKK1-FLAG cells, and cell lysates were immunoprecipitated with anti-HA antibody or nonimmune IgG and probed with anti-p85α and anti-HA antibodies. (D) Amino acid sequence of CKAP4 cytoplasmic region. (E) Lysates of X293T/DKK1-FLAG cells transiently transfected with CKAP4-HA or PA mutant–CKAP4-HA were immunoprecipitated with anti-HA antibody or nonimmune IgG and probed with anti-p85α and anti-HA antibodies. (F) Lysates of X293T/DKK1-FLAG cells transiently transfected with WT or deletion mutant GFP-p85α were immunoprecipitated with anti-CKAP4 antibody or nonimmune IgG and probed with anti-GFP and anti-CKAP4 antibodies. (G) Schematic illustration of human p85α deletion mutants used in this study.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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