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Endocannabinoids are conserved inhibitors of the Hedgehog pathway
#MMPMID25733905
Khaliullina H
; Bilgin M
; Sampaio JL
; Shevchenko A
; Eaton S
Proc Natl Acad Sci U S A
2015[Mar]; 112
(11
): 3415-20
PMID25733905
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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.
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