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