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Endocannabinoids are conserved inhibitors of the Hedgehog pathway.

ABSTRACT: Hedgehog ligands control tissue development and homeostasis by alleviating repression of Smoothened, a seven-pass transmembrane protein. The Hedgehog receptor, Patched, is thought to regulate the availability of small lipophilic Smoothened repressors whose identity is unknown. Lipoproteins contain lipids required to repress Smoothened signaling in vivo. Here, using biochemical fractionation and lipid mass spectrometry, we identify these repressors as endocannabinoids. Endocannabinoids circulate in human and Drosophila lipoproteins and act directly on Smoothened at physiological concentrations to repress signaling in Drosophila and mammalian assays. Phytocannabinoids are also potent Smo inhibitors. These findings link organismal metabolism to local Hedgehog signaling and suggest previously unsuspected mechanisms for the physiological activities of cannabinoids.

SUBMITTER: Khaliullina H

PROVIDER: S-EPMC4371992 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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Endocannabinoids are conserved inhibitors of the Hedgehog pathway.

Khaliullina Helena H Bilgin Mesut M Sampaio Julio L JL Shevchenko Andrej A Eaton Suzanne S

Proceedings of the National Academy of Sciences of the United States of America 20150302 11

Hedgehog ligands control tissue development and homeostasis by alleviating repression of Smoothened, a seven-pass transmembrane protein. The Hedgehog receptor, Patched, is thought to regulate the availability of small lipophilic Smoothened repressors whose identity is unknown. Lipoproteins contain lipids required to repress Smoothened signaling in vivo. Here, using biochemical fractionation and lipid mass spectrometry, we identify these repressors as endocannabinoids. Endocannabinoids circulate ...[more]

PMID: 25733905

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