Regulation of Hedgehog signaling

A complex story

Stacey K. Ogden, Manuel Ascano, Melanie A. Stegman, David J Robbins

Research output: Contribution to journalArticle

73 Citations (Scopus)

Abstract

The Hedgehog (Hh) signal transduction pathway plays critical instructional roles during development. Activating mutations in human Hh signaling components predispose to a variety of tumor types, and have been observed in sporadic tumors occurring in a wide range of organs. Multiple insights into the regulation of Hh signaling have been achieved through studies using Drosophila melanogaster as a model organism. In Drosophila, regulation of the transcription factor Cubitus interruptus (Ci) is the ultimate target of the Hh pathway. Ci is regulated through communication of the membrane proteins Patched (Ptc) and Smoothened (Smo) to the intracellular Hedgehog Signaling Complex (HSC) in response to a graded concentration of Hh ligand. The HSC consists of the Kinesin Related Protein, Costal2 (Cos2), the serine-threonine protein kinase, Fused (Fu) and Ci. In the absence of Hh stimulation, the HSC is involved in processing of Ci to a truncated repressor protein. In response to Hh binding to Ptc, processing of Ci is blocked to allow for accumulation of full-length Ci activator protein(s). Differential concentrations of Hh ligand stimulate production of Ci transcriptional activators of varying strength, which facilitate activation of distinct subsets of target genes. The mechanism(s) by which Ptc and Smo communicate with the HSC in response to differential ligand concentrations to regulate Ci function are not yet fully elucidated. Here, we review what is known about regulation of individual Hh signaling components, concentrating on the mechanisms by which the Hh signal is propagated through Smo to the HSC.

Original languageEnglish
Pages (from-to)805-814
Number of pages10
JournalBiochemical Pharmacology
Volume67
Issue number5
DOIs
StatePublished - Mar 1 2004
Externally publishedYes

Fingerprint

Hedgehogs
Ligands
Tumors
Repressor Proteins
Kinesin
Signal transduction
Protein-Serine-Threonine Kinases
Processing
Membrane Proteins
Proteins
Transcription Factors
Genes
Chemical activation
Communication
Drosophila melanogaster
Drosophila

Keywords

  • Cancer
  • Development
  • Hedgehog
  • Regulation
  • Signal transduction
  • Signaling

ASJC Scopus subject areas

  • Pharmacology

Cite this

Regulation of Hedgehog signaling : A complex story. / Ogden, Stacey K.; Ascano, Manuel; Stegman, Melanie A.; Robbins, David J.

In: Biochemical Pharmacology, Vol. 67, No. 5, 01.03.2004, p. 805-814.

Research output: Contribution to journalArticle

Ogden, Stacey K. ; Ascano, Manuel ; Stegman, Melanie A. ; Robbins, David J. / Regulation of Hedgehog signaling : A complex story. In: Biochemical Pharmacology. 2004 ; Vol. 67, No. 5. pp. 805-814.
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