Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Alerts
  • Advertising/recruitment
  • Subscribe
  • Contact
  • Current Issue
  • Past Issues
  • By specialty
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All...
  • Videos
    • Conversations with Giants in Medicine
    • Author's Takes
  • Reviews
    • View all reviews...
    • Mechanisms Underlying the Metabolic Syndrome (Oct 2019)
    • Reparative Immunology (Jul 2019)
    • Allergy (Apr 2019)
    • Biology of familial cancer predisposition syndromes (Feb 2019)
    • Mitochondrial dysfunction in disease (Aug 2018)
    • Lipid mediators of disease (Jul 2018)
    • Cellular senescence in human disease (Apr 2018)
    • View all review series...
  • Collections
    • Recently published
    • In-Press Preview
    • Commentaries
    • Concise Communication
    • Editorials
    • Viewpoint
    • Scientific Show Stoppers
    • Top read articles
  • Clinical Medicine
  • JCI This Month
    • Current issue
    • Past issues

  • About
  • Editors
  • Consulting Editors
  • For authors
  • Current issue
  • Past issues
  • By specialty
  • Subscribe
  • Alerts
  • Advertise
  • Contact
  • Conversations with Giants in Medicine
  • Author's Takes
  • Recently published
  • Brief Reports
  • Technical Advances
  • Commentaries
  • Editorials
  • Hindsight
  • Review series
  • Reviews
  • The Attending Physician
  • First Author Perspectives
  • Scientific Show Stoppers
  • Top read articles
  • Concise Communication
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.
View: Text | PDF
Category: Commentary

CKAP4 is identified as a receptor for Dickkopf in cancer cells

  • Text
  • PDF
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

×

Figure 1

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

Options: View larger image (or click on image) Download as PowerPoint
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).
Follow JCI:
Copyright © 2019 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts