title: Beta-arrestin-mediated localization of smoothened to the primary cilium.
abstract: beta-Arrestins have important roles in the regulation of seven-transmembrane receptors (7TMRs). Smoothened (Smo) is a 7TMR that mediates effects of Hedgehog on developmental processes and whose dysregulation may cause tumorigenesis. beta-Arrestins are required for endocytosis of Smo and signaling to Gli transcription factors. In mammalian cells, Smo-dependent signaling requires translocation to primary cilia. We demonstrated that beta-arrestins mediate the activity-dependent interaction of Smo and the kinesin motor protein Kif3A. This multimeric complex localized to primary cilia and was disrupted in cells transfected with beta-arrestin small interfering RNA. beta-Arrestin 1 or beta-arrestin 2 depletion prevented the localization of Smo to primary cilia and the Smo-dependent activation of Gli. These results suggest roles for beta-arrestins in mediating the intracellular transport of a 7TMR to its obligate subcellular location for signaling.
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Kovacs
authors.forename: Erin J
authors.initials: EJ
authors.lastname: Whalen
authors.forename: Renshui
authors.initials: R
authors.lastname: Liu
authors.forename: Kunhong
authors.initials: K
authors.lastname: Xiao
authors.forename: Jihee
authors.initials: J
authors.lastname: Kim
authors.forename: Minyong
authors.initials: M
authors.lastname: Chen
authors.forename: Jiangbo
authors.initials: J
authors.lastname: Wang
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Lefkowitz
mesh_terms: D000818:Animals; D019390:Arrestins / Q000235:genetics / Q000378:metabolism*; D002923:Cilia / Q000378:metabolism*; D053823:Hedgehog Proteins / Q000378:metabolism; D016547:Kinesins / Q000378:metabolism*; D051379:Mice; D018613:Microscopy, Confocal; D020409:Molecular Motor Proteins / Q000378:metabolism*; D041681:NIH 3T3 Cells; D021381:Protein Transport; D034622:RNA Interference; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction; D000072086:Smoothened Receptor; D014157:Transcription Factors / Q000378:metabolism; D014162:Transfection; D000071559:beta-Arrestin 1; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins
chemical_list: C000605255:Arrb1 protein, mouse; C000605258:Arrb2 protein, mouse; D019390:Arrestins; D053823:Hedgehog Proteins; C490202:Kif3a protein, mouse; D020409:Molecular Motor Proteins; D043562:Receptors, G-Protein-Coupled; D011993:Recombinant Fusion Proteins; C465570:Shh protein, mouse; C491022:Smo protein, mouse; D000072086:Smoothened Receptor; D014157:Transcription Factors; D000071559:beta-Arrestin 1; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins; C074152:kinesin-II; D016547:Kinesins