SmoothenedWear Sunscreen – stay smooth
Smoothened looks like a GPCR
Hedgehog pathway -- Drosophila
Adapted from Tabata T, et al.
Adapted from Perrimon N, et al.
Hedgehog binds Patched to relievePatched inhibition of Smo
Ingham PW, et al.
Phosphorylation
Shao Y, et al.
Regulated by graded hedgehog signal
Hedgehog Signal Transduction in Mammals
Tabata, T.
Knockout Mouse
Zhang XM, et al.
• Regulates epidermal stem cell population
Smo – stem cell maintenance
Smo
Ptc1
Zhou J, et al.
Basal Cell Carcinoma
Theskincancerfoundation.org
Activated smoothened in Basal Cell Carcinoma
• G-T transversion at 1604 bp –leucine > tryptophan
• G-A transition at 1685 bp – encodes glutamine > arginine
Xie J, et al.
Mutant SMO Transgenic Mice
Grachtchouk V, et al.
SMOH mut – like human BCCs?
Grachtchouk V, et al.
SMOH as a therapeutic targetCyclopamine
Bale AE
Veratrum californicum
Cyclopamine hates Smo
Adapted from Chen JK, et al.
SMOH as a therapeutic target
Adapted from Arthar M, et al.
Treatment of Human BCCs
Adapted from Sinan TS, et al.
Future Directions
• Investigate smoothened – role in other cancers
• Target smoothened for therapy