Smoothened is a protein that in humans is encoded by the SMO gene. It is one of the Class Frizzled (Class F) G protein-coupled receptors. It participates in the hedgehog signaling pathway and can be easily conserved from flies to humans. It is the target of the natural teratogen cyclopamine and Vismodegib, which is the first hedgehog pathway inhibitor approved by the U.S. Food and Drug Administration (FDA).
|Basic Information of SMO|
|Protein Name||Smoothened homolog|
|Organism||Homo sapiens (Human)|
Cellular localization effectively regulates the function of SMO. Stimulation of this transmembrane receptor may bring about translocation of SMO to the primary cilium in vertebrates in the exit of patched from the primary cilium. Vertebrate SMO mutation often cannot contribute to hedgehog pathway activation. However, SMO can positively regulate pathway signaling after a tryptophan to leucine mutation in the aforementioned domain. It has been shown that SMO moves from the plasma membrane near the primary cilium to the ciliary membrane itself via a lateral transport pathway, which is opposed to via directed transport by vesicles. The cAMP-PKA pathway is proven to promote the lateral movement of SMO and hedgehog signal transduction in general. After cellular localization, SMO will then be activated by a distinct mechanism to stimulate hedgehog signal transduction, but the mechanism is still unclear. It seems that the existence of an unidentified endogenous ligand can bind SMO and activate it. It is believed that mutations of SMO can copy the ligand-induced conformation of SMO and in further activate constitutive signal transduction.
Fig.1 Structure of Smoothened homolog.
This article shows that smoothened mutations can serve as a mechanism of drug resistance in human cancer.
The results of this study suggest that change of hedgehog signaling may contribute to breast cancer development by promoting proliferation and increasing the pool of division-competent cells.
This article suggests that cyclopamine and CUR0199691 have unique secondary molecular targets at the dosages required for growth inhibition that are unrelated to smoothened.
The article suggests that two mutations of SMO may be under different mechanisms directing primary and secondary resistance to vismodegib, respectively.
The authors find a purine derivative to activate the Hh pathway and can affect osteoblast differentiation. They demonstrate that smoothened is the direct target of purmorphamine.
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