Activity-dependent internalization of smoothened mediated by beta-arrestin 2 and GRK2.

Published

Journal Article

Binding of Sonic Hedgehog (Shh) to Patched (Ptc) relieves the latter's tonic inhibition of Smoothened (Smo), a receptor that spans the cell membrane seven times. This initiates signaling which, by unknown mechanisms, regulates vertebrate developmental processes. We find that two molecules interact with mammalian Smo in an activation-dependent manner: G protein-coupled receptor kinase 2 (GRK2) leads to phosphorylation of Smo, and beta-arrestin 2 fused to green fluorescent protein interacts with Smo. These two processes promote endocytosis of Smo in clathrin-coated pits. Ptc inhibits association of beta-arrestin 2 with Smo, and this inhibition is relieved in cells treated with Shh. A Smo agonist stimulated and a Smo antagonist (cyclopamine) inhibited both phosphorylation of Smo by GRK2 and interaction of beta-arrestin 2 with Smo. beta-Arrestin 2 and GRK2 are thus potential mediators of signaling by activated Smo.

Full Text

Duke Authors

Cited Authors

  • Chen, W; Ren, X-R; Nelson, CD; Barak, LS; Chen, JK; Beachy, PA; de Sauvage, F; Lefkowitz, RJ

Published Date

  • December 2004

Published In

Volume / Issue

  • 306 / 5705

Start / End Page

  • 2257 - 2260

PubMed ID

  • 15618519

Pubmed Central ID

  • 15618519

Electronic International Standard Serial Number (EISSN)

  • 1095-9203

International Standard Serial Number (ISSN)

  • 0036-8075

Digital Object Identifier (DOI)

  • 10.1126/science.1104135

Language

  • eng