Disease relevance of Smo

• Mutations affecting the transmembrane proteins Patched (Ptc) or Smoothened (Smo) that trigger ligand-independent activity of the Hedgehog (Hh) signalling pathway are associated with human tumours such as basal cell carcinoma (BCC) and medulloblastoma [1].
• Activation of G(i) by Smo is essential in the activation of Gli in fibroblasts, because disruption of coupling to G(i) with pertussis toxin inhibits the activation of Gli by Sonic hedgehog and a constitutively active form of Smo (SmoM2) [2].
• SMO is ectopically expressed in 70% of DCIS and 30% of IBC [3].

High impact information on Smo

• We further find that sterol depletion affects the activity of Smoothened (Smo), an essential component of the Hh signal transduction apparatus [4].
• Despite extensive genetic studies demonstrating the importance of these receptor components in embryonic patterning and cancer, the mechanism by which Ptc regulates Smo is not understood [1].
• Epistasis analyses reveal that Tectonic modulates Hh signal transduction downstream of Smoothened (Smo) and Rab23 [5].
• However, whereas these cell identities are restored in Gli3/Smo compound mutants, correct stratification of the rescued ventral cell types is lost [6].
• Using a chimeric approach, we examined the behavior of Smo null mutant neural progenitor cells in the developing vertebrate spinal cord, and we show that direct Hh signaling is essential for the specification of all ventral progenitor populations [6].

Biological context of Smo

• The phenotypes of the IFT mutants, however, are not identical to mutants that lack Smoothened (Smo), an essential activator of the Hh pathway [7].
• To distinguish between these two alternatives and extend our understanding of Shh's actions in odontogenesis, we have used the Cre-loxP system to remove Smoothened (Smo) activity in the dental epithelium [8].
• These data indicate that primary cilia act as specialized signal transduction organelles required for coupling Smo activity to the biochemical processing of Gli3 protein [9].
• The deduced amino acid sequence of mSmo consisted of 793 amino acids and was 98 and 93% homologous to the rat (r) Smo and human (h) Smo, respectively [10].
• We show that one consequence of pre-TCR signaling is downregulation of Smo, allowing DN thymocytes to proliferate and differentiate [11].

Anatomical context of Smo

• Cyclopamine had particularly potent effects of inhibiting the growth of cell lines that expressed high levels of SMO [12].
• Consistent with Hedgehog signaling being required for the maintenance of stem cell niches in the adult brain, progenitors from the subventricular zone of floxed Smo animals formed significantly fewer neurospheres [13].
• Smo(-/-) yolk sacs arrest at an earlier stage: the endothelial tubes are packed with hematopoietic cells, and fail to undergo even the limited vascular remodeling observed in the Ihh(-/-) yolk sacs [14].
• In order to discern the direct versus indirect roles of Ihh in cartilage development, we have used the Cre-loxP approach to remove Smo activity specifically in chondrocytes [15].
• In order to determine whether Ihh is directly required for osteoblast differentiation, we have genetically manipulated smoothened (Smo), which encodes a transmembrane protein that is essential for transducing all Hedgehog (Hh) signals [16].

Physical interactions of Smo

• CONCLUSIONS: These data demonstrate that Smo is the signaling component of a multicomponent Hh receptor complex and that Ptc is a ligand-regulated inhibitor of Smo [17].

Regulatory relationships of Smo

• Hence, removal of Smo activity from the dental epithelium should block Shh signaling within dental epithelial derivatives while preserving normal mesenchymal signaling [8].

Other interactions of Smo

• The inhibition of Smo by Ptc can be relieved by the addition of Shh [17].
• Furthermore, oncogenic forms of Smo are insensitive to Ptc repression in this assay [17].
• To address the nature of the possible vascular defects, we have examined the ability of ES cells deficient for Ihh or smoothened (Smo), which encodes a receptor component essential for all hedgehog signaling, to form blood islands in vitro [14].
• Loss of the retrograde motor for IFT disrupts localization of Smo to cilia and prevents the expression of both activator and repressor functions of Gli [9].
• Genetic analyses have now shown that Rab23 functions downstream of Smo and affects the function of the Shh-regulated Gli family of transcription factors in a more direct manner than previously thought [18].

Analytical, diagnostic and therapeutic context of Smo

• These findings indicate that propagation of tumor cells in culture inhibits Smo activity in a way that cannot be reversed by transplantation in vivo, and they raise concerns about the use of cultured tumor cells to test the efficacy of Shh pathway inhibitors as anticancer therapies [19].
• Oocytes are unable to respond to hedgehog because they lack expression of the essential signal transducer Smo (smoothened) [20].
• In the present study, we showed by Northern analysis and in situ hybridization that Smoothened (Smo), a key component in hedgehog signal transduction, was expressed in chondrocytes in both adult mice and mouse embryos at 16 days post-coitum in vivo, suggesting that Ihh directly acts on chondrocytes [21].

References