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Updated: Mar 19, 2026
Three-Dimensional 3D Tumor Spheroid Invasion Assay
Published on: May 1, 2015
CKAP4 is a Dickkopf1 receptor and is involved in tumor progression
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.
Insights
Cytoskeleton-associated protein 4 (CKAP4) acts as a Dickkopf1 (DKK1) receptor, driving cancer cell proliferation through AKT signaling. Targeting CKAP4 may offer a new therapeutic strategy for DKK1-expressing cancers.
Area of Science:
- Oncology
- Molecular Biology
- Cell Signaling
Background:
- Dickkopf1 (DKK1) antagonizes Wnt signaling via low-density lipoprotein receptor-related protein 6 (LRP6).
- DKK1's role in promoting cancer cell proliferation via its own signaling pathway remains unclear.
Purpose of the Study:
- Identify the receptor for DKK1's self-signaling pathway.
- Investigate the mechanism of DKK1-mediated cancer cell proliferation.
- Evaluate the therapeutic potential of targeting this pathway.
Main Methods:
- Protein binding assays to identify DKK1 receptor.
- Clathrin-dependent internalization assays.
- Western blotting and co-immunoprecipitation to analyze signaling complexes.
- Analysis of patient tumor samples for DKK1 and CKAP4 expression.
- In vivo xenograft studies with anti-CKAP4 antibody treatment.
Main Results:
- Cytoskeleton-associated protein 4 (CKAP4) identified as a DKK1 receptor, binding with similar affinity to LRP6.
- DKK1 binding to CKAP4 triggers clathrin-dependent internalization.
- DKK1/CKAP4 signaling activates AKT pathway via CKAP4-PI3K interaction, promoting cell proliferation.
- High DKK1 and CKAP4 expression in pancreatic and lung cancers correlates with poor prognosis.
- Anti-CKAP4 antibody inhibits DKK1 binding, suppresses AKT activity, and reduces tumor growth.
Conclusions:
- CKAP4 is a functional receptor for DKK1, mediating cancer cell proliferation.
- The DKK1/CKAP4/AKT signaling axis represents a novel mechanism in cancer.
- CKAP4 is a promising therapeutic target for DKK1- and CKAP4-expressing cancers.
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