or 
Receptor Family
Patched
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Summary

Patched receptors have 12 membrane-traversing domains. They are unique among plasma membrane receptors because they have no identified intrinsic enzymatic activity or recruiter function. Patched receptors are activated by the hedgehog family of ligands, which is modified by the covalent attachment of a cholesterol moiety and suppress the function of smoothened, a 7TM protein. Smoothened, in turn, regulates the proteolytic cleavage of cubitus interruptus (Ci), a transcriptional repressor (99). Ligand activation of patched suppresses proteolysis induced by smoothened, causing a relief of the repressor function of Ci. In C. elegans and D. melanogaster, several genes related to patched and hedgehog exist (100, 101). Mutations in human patched and smoothened genes are associated with basal cell carcinoma (102). Patched does not dimerize with smoothened and is structurally related to a bacterial transmembrane transporter and to human Niemann-Pick type C disease gene product, a cholesterol transporter (103). Thus, patched may function as a transporter, and ligand binding of patched could change the distribution or concentration of a small molecule (104). Patched may represent the fading boundary between classic receptors (that bind external ligands and activate separate intracellular components) and transporters and channels (that move components across the membrane, thus signaling by altering the concentration of signaling molecules across the membrane). Of course, many receptors, not discussed here, are ligand-gated ion channels that serve to initiate signaling cascades by altering the concentration of ions across the plasma membrane.
Relevant reviews and publications:
99. P. Aza-Blanc, F. A. Ramirez-Weber, M. P. Laget, C. Schwartz, T. B. Kornberg, Proteolysis that is inhibited by hedgehog targets Cubitus interruptus protein to the nucleus and converts it to a repressor. Cell 89, 1043-1053 (1997). 100. G. Aspock, H. Kagoshima, G. Niklaus, T. R. Burglin, Caenorhabditis elegans has scores of hedgehog-related genes: sequence and expression analysis. Genome Res 9, 909-923 (1999). 101. P. W. Ingham, Localized hedgehog activity controls spatial limits of wingless transcription in the Drosophila embryo. Nature 366, 560-562 (1993). 102. J. Xie, M. Murone, S. M. Luoh, A. Ryan, Q. Gu, C. Zhang, J. M. Bonifas, C. W. Lam, M. Hynes, A. Goddard, et al., Activating Smoothened mutations in sporadic basal-cell carcinoma. Nature 391, 90-92 (1998). 103. P. E. Kuwabara, M. Labouesse, The sterol-sensing domain: multiple families, a unique role? Trends Genet 18, 193-201 (2002). 104. J. Taipale, M. K. Cooper, T. Maiti, P. A. Beachy, Patched acts catalytically to suppress the activity of Smoothened. Nature 418, 892-897 (2002).
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