Editors' ChoiceDevelopment

Hedgehog, Smoothened, and β-Arrestin

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Science's STKE  04 Jan 2005:
Vol. 2005, Issue 265, pp. tw7
DOI: 10.1126/stke.2652005tw7

Hedgehog (Hh) proteins carry signals that are essential for pattern formation during vertebrate embryogenesis. Extracellular Hh molecules bind to a receptor on the cell surface and activate Smoothened, a membrane-spanning protein, which transmits signals to the cell interior. β-Arrestin proteins are inhibitors of heterotrimeric GTP-binding protein (G protein)-coupled receptor (GPCR) signaling and also promote internalization and signaling by GPCRs. Chen et al. find that in mammalian cells, activated Smoothened molecules preferentially associate with β-arrestin 2. Reducing levels of β-arrestin 2 inhibited internalization of Smoothened. Furthermore, Wilbanks et al. find that loss of β-arrestin 2 in zebrafish causes developmental abnormalities similar to those of mutants in the Hh signaling pathway. Overexpression of β-arrestin 2 could partially rescue some defects in embryos with deficient Hh signaling, and loss of β-arrestin 2 decreased expression of Hh-responsive genes. Together, the findings provide insight into the roles of β-arrestin 2 during development and the mechanisms by which Hh signaling influences developmental processes from embryogenesis to cancer.

W. Chen, X.-R. Ren, C. D. Nelson, L. S. Barak, J. K. Chen, P. A. Beachy, F. de Sauvage, R. J. Lefkowitz, Activity-dependent internalization of Smoothened mediated by β-arrestin 2 and GRK2. Science 306, 2257-2260 (2004). [Abstract] [Full Text]

A. M. Wilbanks, G. B. Fralish, M. L. Kirby, L. S. Barak, Y.-X. Li, M. G. Caron, β-Arrestin 2 regulates zebrafish development through the Hedgehog signaling pathway. Science 306, 2264-2267 (2004). [Abstract] [Full Text]