Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • Vascular Malformations (Apr 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
Misactivation of Hedgehog signaling causes inherited and sporadic cancers
David R. Raleigh, Jeremy F. Reiter
David R. Raleigh, Jeremy F. Reiter
Published February 1, 2019
Citation Information: J Clin Invest. 2019;129(2):465-475. https://doi.org/10.1172/JCI120850.
View: Text | PDF
Review Series

Misactivation of Hedgehog signaling causes inherited and sporadic cancers

  • Text
  • PDF
Abstract

The Hedgehog pathway is critical for the development of diverse organs. Misactivation of the Hedgehog pathway can cause developmental abnormalities and cancers, including medulloblastoma, the most common pediatric brain tumor, and basal cell carcinoma, the most common cancer in the United States. Here, we review how basic, translational, and clinical studies of the Hedgehog pathway have helped reveal how cells communicate, how intercellular communication controls development, how signaling goes awry to cause cancer, and how to use targeted molecular agents to treat both inherited and sporadic cancers.

Authors

David R. Raleigh, Jeremy F. Reiter

×

Figure 1

A model of ciliary Hedgehog signaling.

Options: View larger image (or click on image) Download as PowerPoint
A model of ciliary Hedgehog signaling.
(A) In the absence of Hedgehog li...
(A) In the absence of Hedgehog ligands such as SHH, PTCH1 localizes to the primary cilium and, through an unknown mechanism, prevents SMO from entering the cilium. GLI proteins bind SUFU, a negative regulator, and are phosphorylated by kinases, such as PKA, to generate transcriptional repressors that enter the nucleus and silence the Hedgehog transcriptional program. (B) In the presence of SHH, PTCH1 leaves the cilium, allowing SMO to accumulate at the primary cilium membrane. At the cilium, SMO inhibits the formation of GLI3 repressor and activates GLI2, which enters the nucleus to promote transcription of Hedgehog target genes. (C) Inactivating mutations in PTCH1, PTCH2, or SUFU; activating mutations in SMO (denoted here as an asterisk); or amplification of GLI2 can activate expression of Hedgehog target genes in an unregulated way, leading to cancer.

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

Sign up for email alerts