Beta-arrestin-mediated localization of smoothened to the primary cilium

Science. 2008 Jun 27;320(5884):1777-81. doi: 10.1126/science.1157983. Epub 2008 May 22.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arrestins / genetics
  • Arrestins / metabolism*
  • Cilia / metabolism*
  • Hedgehog Proteins / metabolism
  • Kinesins / metabolism*
  • Mice
  • Microscopy, Confocal
  • Molecular Motor Proteins / metabolism*
  • NIH 3T3 Cells
  • Protein Transport
  • RNA Interference
  • Receptors, G-Protein-Coupled / metabolism*
  • Recombinant Fusion Proteins / metabolism
  • Signal Transduction
  • Smoothened Receptor
  • Transcription Factors / metabolism
  • Transfection
  • beta-Arrestin 1
  • beta-Arrestin 2
  • beta-Arrestins

Substances

  • Arrb1 protein, mouse
  • Arrb2 protein, mouse
  • Arrestins
  • Hedgehog Proteins
  • Kif3a protein, mouse
  • Molecular Motor Proteins
  • Receptors, G-Protein-Coupled
  • Recombinant Fusion Proteins
  • Shh protein, mouse
  • Smo protein, mouse
  • Smoothened Receptor
  • Transcription Factors
  • beta-Arrestin 1
  • beta-Arrestin 2
  • beta-Arrestins
  • kinesin-II
  • Kinesins