Smoothened

Signal transduction pathways

Smo SterolBindingSites

Smoothened (SMO) is a protein that in humans is encoded by the SMO gene. It is a key component in the Hedgehog signaling pathway, which is involved in the development of animals from flies to humans and is implicated in the regulation of cell growth and morphogenesis. The pathway is named after its ligand, the secreted protein Hedgehog (Hh), and Smoothened is responsible for transducing the Hedgehog signal across the cell membrane.

Function

Smoothened is a G protein-coupled receptor (GPCR) that is activated by the Hedgehog ligand. In the absence of Hedgehog, Smoothened is inhibited by another protein called Patched (PTCH1). When Hedgehog binds to Patched, this inhibition is relieved, allowing Smoothened to activate the downstream components of the signaling pathway. This activation leads to the transcription of target genes involved in cell proliferation, differentiation, and survival.

Role in Development and Disease

The Hedgehog signaling pathway, with Smoothened as a central component, plays a critical role in embryonic development. It is involved in the formation of the limbs, the neural tube, and many other tissues. Mutations in components of the pathway, including Smoothened, can lead to developmental disorders and diseases. For example, mutations in the SMO gene have been associated with nevoid basal cell carcinoma syndrome (Gorlin syndrome), a condition characterized by the development of multiple basal cell carcinomas and other abnormalities.

In addition to its role in development, aberrant activation of Smoothened and the Hedgehog pathway has been implicated in the pathogenesis of various cancers, including basal cell carcinoma, medulloblastoma, and others. This has led to the development of Smoothened inhibitors as therapeutic agents in cancer treatment.

Smoothened Inhibitors

Several inhibitors of Smoothened have been developed for use in cancer therapy. These drugs, such as vismodegib and sonidegib, target the Smoothened protein directly, blocking its activity and thus inhibiting the Hedgehog signaling pathway. They are used in the treatment of cancers where the pathway is abnormally activated, such as in advanced basal cell carcinoma.

Structure

The structure of Smoothened is similar to that of other G protein-coupled receptors, with seven transmembrane domains. However, unlike most GPCRs, its activation mechanism does not involve a direct binding of a ligand to the receptor. Instead, its activity is regulated by the presence or absence of the Hedgehog ligand binding to the Patched receptor.

Research Directions

Research on Smoothened and the Hedgehog signaling pathway continues to be a vibrant field, with studies aimed at understanding the detailed mechanisms of pathway activation and inhibition, the role of the pathway in stem cell biology and regeneration, and the development of new therapeutic agents targeting this pathway for the treatment of cancer and other diseases.