Smoothened and The Hedgehog (Hh) Pathway

James (Jay) LomaxBIOL 4453/19/13

What is Smoothened?(a protein conserved in Drosophila and Humans)

Conservation correlates with its important biological function

Biochemical Role of Hedgehog Pathway within the Cell

Stone et al.

Utilized a technique known as: co-immunoprecipitation

Key components of the Hh signaling pathway

Hedgehog Signaling Pathway

What happens when part of the pathway is mutated?

Xie et al.

But what about the other players?

Tumor formation

Biological Role of the Hh Pathway

Drosophila

Biological Role of the Hh Pathway

Mice

Basal Cell Carcinoma

An open sore A reddish patch A shiny bump or nodule

A pink growth A scar-like area

Current Treatments

Hh/Smoothened Pathway Inhibitors

In theory: In reality:

Erivedge (Vismodegib)Cyclopamine

Veratrum californicum

References1. A positive role for Patched-Smoothened signaling in promoting cell proliferation during

normal head development in Drosophila. Baragur V. Shyamala and Krishna Moorthi Bhat2. GLI transcription factors: Mediators of oncogenic Hedgehog signalling. Maria Kasper,

Gerhard Regl, Anna-Maria Frischauf, Fritz Aberger3. Hedgehog-Regulated Processing of Gli3 Produces an Anterior/Posterior Repressor

Gradient in the Developing Vertebrate Limb. Cell, Volume 100, Issue 4, 18 February 2000,

Pages 423–434. Baolin Wang , John F Fallon , Philip A Beachy4. http://www.hedgehogpathway.com5. http://www.skincancer.org6. Stone, D. M., Hynes, M., Armanini, M., Swanson, T. A., Gu, Q., Johnson, R. L., Scott, M. P.,

Pennica, D., Goddard, A., Phillips, H., Noll, M., Hooper, J. E., de Sauvage, F., Rosenthal, A. The tumour-suppressor gene Patched encodes a candidate receptor for Sonic hedgehog. Nature 384: 129-134, 1996.

7. Xie, J., Murone, M., Luoh, S.-M., Ryan, A., Gu, Q., Zhang, C., Bonifas, J. M., Lam, C.-W., Hynes, M., Goddard, A., Rosenthal, A., Epstein, E. H., Jr., de Sauvage, F. J. Activating Smoothened mutations in sporadic basal-cell carcinoma. Nature 391: 90-92, 1998.