smos ar15

Smoothened is a protein that in humans is encoded by the SMO gene. Smoothened is a Class Frizzled (Class F) G protein-coupled receptor that is a component of the hedgehog signaling pathway and is conserved from flies to humans. It is the molecular target of the natural teratogen cyclopamine. It also is the target of vismodegib, the first hedgehog pathway inhibitor to be approved by the U.S. Food and Drug Administration (FDA).Smoothened (Smo) is a key transmembrane protein that is a key component of the hedgehog signaling pathway, a cell-cell communication system critical for embryonic development and adult tissue homeostasis. Mutations in proteins that relay Hh signals between cells cause birth defects and cancer. The protein that carries the Hh signal across the membrane is the oncoprotein and G-protein coupled receptor (GPCR) Smoothened (Smo). Smo is regulated by a separate transmembrane receptor for Hh ligands called Patched (Ptc). Ptc itself is a tumor suppressor that keeps the Hh pathway off by inhibiting Smo. The excessive Hh signaling that drives human skin and brain cancer is most frequently caused by inactivating mutations in Ptc or by gain of function mutations in Smo. While direct Smo agonists and antagonists, such as SAG and vismodegib, can bind to and activate or inhibit Smo, how Ptc inhibits Smo endogenously remains a mystery in the field.
Currently, Smo is targeted and inhibited directly by a small-molecule drug, vismodegib, for the treatment of advanced basal cell cancer, however widespread resistance to this drug has become a prevalent issue. Finding another method to target Smo activity in Hh-driven cancers would provide valuable information for novel therapeutics. Identifying these Ptc responsive sites on Smo will help solve a long-standing mystery in Hh signaling and suggest new therapeutic strategies to block Smo activity in Hh-driven cancers.

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