CKAP4 is identified as a receptor for Dickkopf in cancer cells
Dheeraj Bhavanasi, … , Kelsey F. Speer, Peter S. Klein
Dheeraj Bhavanasi, … , Kelsey F. Speer, Peter S. Klein
Published July 1, 2016; First published June 20, 2016
Citation Information: J Clin Invest. 2016;126(7):2419-2421. https://doi.org/10.1172/JCI88620.
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Category: Commentary

CKAP4 is identified as a receptor for Dickkopf in cancer cells

Abstract

The secretory protein Dickkopf-1 (DKK-1) is a known Wnt antagonist and has been shown to suppress tumorigenesis in some cancer cells; however, it is also upregulated in many types of cancer and associated with poor prognosis. Wnt-independent mechanisms by which DKK-1 promotes cancer cell proliferation are not well understood. In this issue of the JCI, Kimura and colleagues demonstrate that DKK-1 interacts with cytoskeleton-associated protein 4 (CKAP4) to promote activation of AKT. They show that both DKK-1 and CKAP4 are frequently upregulated in pancreatic and lung cancers. Importantly, targeting this interaction with an anti-CKAP4 antibody prevented tumor formation in murine xenograft models. These results identify a previously unrecognized DKK-1–mediated pathway and suggest CKAP4 as a potential therapeutic target for certain cancers.

Authors

Dheeraj Bhavanasi, Kelsey F. Speer, Peter S. Klein

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Figure 1

DKK-1 stimulates proliferation by binding to CKAP4 and activating AKT.

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DKK-1 stimulates proliferation by binding to CKAP4 and activating AKT. D...
DKK-1 is secreted from epithelial cells and binds to the extracellular domain of CKAP4 at the apical surface of the cell. The CRD-1 of DKK-1 and the leucine zipper (LZ) domain of CKAP4 are required for this interaction (although a direct interaction between the two has not yet been shown). Upon DKK-1 binding, CKAP4 binds to the p85α subunit of PI3K to activate PI3K/AKT signaling and stimulate cancer cell proliferation. This signaling motif is in contrast to the well-established role for DKK-1 as a canonical Wnt antagonist, in which CRD-2 of DKK-1 binds to the Wnt coreceptor LRP5/6 (preventing interaction with Wnts) and to Kremen (driving internalization of LRP5/6).