The protein target of a small molecule known to induce stem cell differentiation is reported in a paper in the January issue of Nature Chemical Biology. This molecule, purmorphamine, has been shown to trigger progenitor cell differentiation to osteoblasts, cells that build bones. Purmorphamine was believed to target the Hedgehog signaling pathway, which is involved in many developmental and growth processes in multicellular organisms, including embryonic patterning, tissue regeneration, stem cell renewal and cancer growth. However, the precise target of purmorphamine was not known.
By using a combination of genetics and biochemistry, James Chen and colleagues gradually narrowed down potential targets in the Hedgehog signaling pathway to identify the protein Smoothened as the target.
The authors further show that purmorphamine binds directly to a bundle of membrane-spanning helices. However even with this information about the binding site, future studies will be necessary to characterize the precise mechanism for how purmorphamine activates Smoothened.
Because the Hedgehog signaling pathway is involved in many critical developmental processes and diseases, understanding the mechanism of action of this chemical modulator provides a new lead for developing therapeutics for certain cancers, such as brain tumors, and stem cell treatments, such as bone regeneration.
James Chen (Stanford University, Stanford, CA, USA)
Abstract available online.
(C) Nature Chemical Biology press release.
Message posted by: Trevor M. D'Souza