title: The role of ciliary trafficking in Hedgehog receptor signaling.
abstract: Defects in the biogenesis of or transport through primary cilia affect Hedgehog protein signaling, and many Hedgehog pathway components traffic through or accumulate in cilia. The Hedgehog receptor Patched negatively regulates the activity and ciliary accumulation of Smoothened, a seven-transmembrane protein that is essential for transducing the Hedgehog signal. We found that this negative regulation of Smoothened required the ciliary localization of Patched, as specified either by its own cytoplasmic tail or by provision of heterologous ciliary localization signals. Surprisingly, given that Hedgehog binding promotes the exit of Patched from the cilium, we observed that an altered form of Patched that is retained in the cilium nevertheless responded to Hedgehog, resulting in Smoothened activation. Our results indicate that whereas ciliary localization of Patched is essential for suppression of Smoothened activation, the primary event enabling Smoothened activation is binding of Hedgehog to Patched, and Patched ciliary removal is secondary.
authors.affiliation: Departments of Biochemistry and Developmental Biology, Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA. Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Jynho
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Anatomy and Regenerative Biology, George Washington University School of Medicine and Health Sciences, Washington, DC 20037, USA.
authors.forename: Elaine Y C
authors.initials: EY
authors.lastname: Hsia
authors.affiliation: Institut Jacques Monod, CNRS, UMR 7592, Université Paris Diderot, Sorbonne Paris Cité, F-75205 Paris, France.
authors.forename: Amira
authors.initials: A
authors.lastname: Brigui
authors.affiliation: Institut Jacques Monod, CNRS, UMR 7592, Université Paris Diderot, Sorbonne Paris Cité, F-75205 Paris, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Plessis
authors.affiliation: Departments of Biochemistry and Developmental Biology, Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA. Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA. pbeachy@stanford.edu xzheng@gwu.edu.
authors.forename: Philip A
authors.initials: PA
authors.lastname: Beachy
authors.affiliation: Departments of Biochemistry and Developmental Biology, Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA. Department of Anatomy and Regenerative Biology, George Washington University School of Medicine and Health Sciences, Washington, DC 20037, USA. pbeachy@stanford.edu xzheng@gwu.edu.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Zheng
mesh_terms: D000818:Animals; D002923:Cilia / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D000072079:Patched Receptors; D021381:Protein Transport / Q000502:physiology; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D000072086:Smoothened Receptor
chemical_list: D053823:Hedgehog Proteins; D000072079:Patched Receptors; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; C491023:SMO protein, human; C491022:Smo protein, mouse; D000072086:Smoothened Receptor