The DOI matches its Crossref record; 37 of the 37 references it cites were found in a registry or an index.
Small molecule modulation of Smoothened activity
Open accessAbstract
Smoothened (Smo), a distant relative of G protein-coupled receptors, mediates Hedgehog (Hh) signaling during embryonic development and can initiate or transmit ligand-independent pathway activation in tumorigenesis. Although the cellular mechanisms that regulate Smo function remain unclear, the direct inhibition of Smo by cyclopamine, a plant-derived steroidal alkaloid, suggests that endogenous small molecules may be involved. Here we demonstrate that SAG, a chlorobenzothiophene-containing Hh pathway agonist, binds to the Smo heptahelical bundle in a manner that antagonizes cyclopamine action. In addition, we have identified four small molecules that directly inhibit Smo activity but are structurally distinct from cyclopamine. Functional and biochemical studies of these compounds provide evidence for the small molecule modulation of Smo through multiple mechanisms and yield insights into the physiological regulation of Smo activity. The mechanistic differences between the Smo antagonists may be useful in the therapeutic manipulation of Hh signaling.
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Cites
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Inhibition of Hedgehog signaling by direct binding of cyclopamine to Smoothened
Chen, J. K., Taipale, J., Cooper, M. K., & Beachy, P. A. (2002) · Genes & Development · doi:10.1101/gad.1025302 · Cited by 1,465
Self-citationThe Hedgehog and Wnt signalling pathways in cancer
Taipale, J., & Beachy, P. A. (2001) · Nature · doi:10.1038/35077219 · Cited by 1,393
Self-citationEffects of oncogenic mutations in Smoothened and Patched can be reversed by cyclopamine
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Self-citationThe tumour-suppressor gene patched encodes a candidate receptor for Sonic hedgehog
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An LDL-receptor-related protein mediates Wnt signalling in mice
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G Protein-Coupled Receptor Allosterism and Complexing
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Cited by
Patched1 Regulates Hedgehog Signaling at the Primary Cilium
Rohatgi, R., Milenkovic, L., & Scott, M. P. (2007) · Science · doi:10.1126/science.1139740 · Cited by 1,426
Hedgehog: functions and mechanisms
Varjosalo, M., & Taipale, J. (2008) · Genes & Development · doi:10.1101/gad.1693608 · Cited by 1,217
Self-citationTissue repair and stem cell renewal in carcinogenesis
Beachy, P. A., Karhadkar, S. S., & Berman, D. M. (2004) · Nature · doi:10.1038/nature03100 · Cited by 1,208
Self-citationThe SCF ubiquitin ligase: insights into a molecular machine
Cardozo, T., & Pagano, M. (2004) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm1471 · Cited by 1,114
Hedgehog signalling within airway epithelial progenitors and in small-cell lung cancer
Watkins, D. N., Berman, D. M., Burkholder, S. G., Wang, B., Beachy, P. A., & Baylin, S. B. (2003) · Nature · doi:10.1038/nature01493 · Cited by 1,082
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Metadata
- Authors
- Chen, J. K., Taipale, J., Young, K. E., Maiti, T., & Beachy, P. A.
- Venue
- Proceedings of the National Academy of Sciences
- Published
- 2002-10-21
- Volume
- 99
- Issue
- 22
- Pages
- 14071-14076
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- OpenAlex
- W2090455515
- Cited by
- 992
- References
- 37
- FWCI
- 7.45
- Type
- journal article
- Language
- en
- Open access
- green
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- Chen, J. K., Taipale, J., Young, K. E., Maiti, T., & Beachy, P. A. (2002). Small molecule modulation of Smoothened activity. Proceedings of the National Academy of Sciences. https://doi.org/10.1073/pnas.182542899
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Bibliographic data: Semantic Scholar, OpenAlex, Crossref.
Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
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