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Gene Review

smo  -  smoothened

Drosophila melanogaster

Synonyms: CG11561, Dmel\CG11561, Protein smoothened, SMO, SMOH, ...
 
 
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Disease relevance of smo

  • Hence, mutations within the ptc gene that result in the failure of Ptc to inhibit Smo lead to constitutive activity of the Hh signalling pathway and to cancer, such as basal cell carcinoma [1].
  • We demonstrate that, as in Drosophila, vertebrate smoothened is essential for hedgehog signaling, and functions upstream of protein kinase A. Further analysis of neural tube defects revealed the absence of lateral floor plate and secondary motoneurons, but the presence of medial floor plate and primary motoneurons in smoothened mutant embryos [2].
 

High impact information on smo

 

Biological context of smo

  • These results suggest that Ptc normally binds Hh without any help from Smo and hence favor a mechanism of signal transduction in which Hh binds specifically to Ptc and induces a conformational change leading to the release of latent Smo activity [5].
  • Conversely, Smo becomes constitutively active if acidic residues replace those phosphorylation sites [6].
  • Here we show that the latter response is mediated principally by regulatory elements other than Ci binding sites and not by altered Smo phosphorylation [6].
  • Conversely, trapping of activated Smo mutants in the ER prevents Hh target gene activation [7].
  • All Hh responses require the seven transmembrane domain protein Smoothened, which itself becomes hyperphosphorylated during Hh signalling [8].
 

Anatomical context of smo

 

Associations of smo with chemical compounds

  • Using immunopurification and mass spectrometry, we identify here 26 serine/threonine residues within the Smo C-terminal cytoplasmic tail that are phosphorylated in Hh-stimulated cells [10].
  • Given our present understanding of the Hh signaling pathway, the absence of Hh and Smo raises many questions about the evolution and the function of the PTC, PTR, and Hh-r proteins in C. elegans [11].
  • Mutations in the sterol-sensing domain of Patched suggest a role for vesicular trafficking in Smoothened regulation [12].
  • Since Hh has been found in lipid rafts in Drosophila, we hypothesized that Patched and Smoothened might also be found in these cholesterol-rich microdomains [13].
  • We also provide experiments showing that human Smo, when expressed in Schneider cells, is able to bind the alkaloid cyclopamine, suggesting that it is expressed in a native conformational state [14].
 

Physical interactions of smo

  • We also show that Cos2 binding on Smo is necessary for the Hh-dependent dissociation of Ci from this complex [9].
  • In vivo evidence that Patched and Smoothened constitute distinct binding and transducing components of a Hedgehog receptor complex [5].
  • It is not known how the Hedgehog signal is relayed from Smoothened to the regulatory complex nor how responses to different levels of Hedgehog are implemented [15].
 

Regulatory relationships of smo

 

Other interactions of smo

 

Analytical, diagnostic and therapeutic context of smo

References

  1. Hedgehog and its patched-smoothened receptor complex: a novel signalling mechanism at the cell surface. Alcedo, J., Noll, M. Biol. Chem. (1997) [Pubmed]
  2. Analysis of the zebrafish smoothened mutant reveals conserved and divergent functions of hedgehog activity. Chen, W., Burgess, S., Hopkins, N. Development (2001) [Pubmed]
  3. Hedgehog induces opposite changes in turnover and subcellular localization of patched and smoothened. Denef, N., Neubüser, D., Perez, L., Cohen, S.M. Cell (2000) [Pubmed]
  4. The Drosophila smoothened gene encodes a seven-pass membrane protein, a putative receptor for the hedgehog signal. Alcedo, J., Ayzenzon, M., Von Ohlen, T., Noll, M., Hooper, J.E. Cell (1996) [Pubmed]
  5. In vivo evidence that Patched and Smoothened constitute distinct binding and transducing components of a Hedgehog receptor complex. Chen, Y., Struhl, G. Development (1998) [Pubmed]
  6. The contributions of protein kinase A and smoothened phosphorylation to hedgehog signal transduction in Drosophila melanogaster. Zhou, Q., Apionishev, S., Kalderon, D. Genetics (2006) [Pubmed]
  7. Altered localization of Drosophila Smoothened protein activates Hedgehog signal transduction. Zhu, A.J., Zheng, L., Suyama, K., Scott, M.P. Genes Dev. (2003) [Pubmed]
  8. Drosophila Smoothened phosphorylation sites essential for Hedgehog signal transduction. Apionishev, S., Katanayeva, N.M., Marks, S.A., Kalderon, D., Tomlinson, A. Nat. Cell Biol. (2005) [Pubmed]
  9. Stability and association of Smoothened, Costal2 and Fused with Cubitus interruptus are regulated by Hedgehog. Ruel, L., Rodriguez, R., Gallet, A., Lavenant-Staccini, L., Thérond, P.P. Nat. Cell Biol. (2003) [Pubmed]
  10. Extensive phosphorylation of Smoothened in Hedgehog pathway activation. Zhang, C., Williams, E.H., Guo, Y., Lum, L., Beachy, P.A. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  11. The function and expansion of the Patched- and Hedgehog-related homologs in C. elegans. Zugasti, O., Rajan, J., Kuwabara, P.E. Genome Res. (2005) [Pubmed]
  12. Mutations in the sterol-sensing domain of Patched suggest a role for vesicular trafficking in Smoothened regulation. Strutt, H., Thomas, C., Nakano, Y., Stark, D., Neave, B., Taylor, A.M., Ingham, P.W. Curr. Biol. (2001) [Pubmed]
  13. The sonic hedgehog receptor patched associates with caveolin-1 in cholesterol-rich microdomains of the plasma membrane. Karpen, H.E., Bukowski, J.T., Hughes, T., Gratton, J.P., Sessa, W.C., Gailani, M.R. J. Biol. Chem. (2001) [Pubmed]
  14. Human receptors patched and smoothened partially transduce hedgehog signal when expressed in Drosophila cells. De Rivoyre, M., Ruel, L., Varjosalo, M., Loubat, A., Bidet, M., Thérond, P., Mus-Veteau, I. J. Biol. Chem. (2006) [Pubmed]
  15. Smoothened translates Hedgehog levels into distinct responses. Hooper, J.E. Development (2003) [Pubmed]
  16. Fused-Costal2 protein complex regulates Hedgehog-induced Smo phosphorylation and cell-surface accumulation. Liu, Y., Cao, X., Jiang, J., Jia, J. Genes Dev. (2007) [Pubmed]
  17. Smoothened regulates activator and repressor functions of Hedgehog signaling via two distinct mechanisms. Ogden, S.K., Casso, D.J., Ascano, M., Yore, M.M., Kornberg, T.B., Robbins, D.J. J. Biol. Chem. (2006) [Pubmed]
  18. smoothened encodes a receptor-like serpentine protein required for hedgehog signalling. van den Heuvel, M., Ingham, P.W. Nature (1996) [Pubmed]
  19. Reading the Hedgehog morphogen gradient by measuring the ratio of bound to unbound Patched protein. Casali, A., Struhl, G. Nature (2004) [Pubmed]
 
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