DEVELOPMENT Hedgehog, Smoothened, and ß-Arrestin

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. ß-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 ß-arrestin 2. Reducing levels of ß-arrestin 2 inhibited internalization of Smoothened. Furthermore, Wilbanks et al. find that loss of ß-arrestin 2 in zebrafish causes developmental abnormalities similar to those of mutants in the Hh signaling pathway. Overexpression of ß-arrestin 2 could partially rescue some defects in embryos with deficient Hh signaling, and loss of ß-arrestin 2 decreased expression of Hh-responsive genes. Together, the findings provide insight into the roles of ß-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 ß-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, ß-Arrestin 2 regulates zebrafish development through the Hedgehog signaling pathway. Science 306, 2264-2267 (2004). [Abstract] [Full Text]

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DEVELOPMENT
Smoothened Phosphorylation Promotes Hedgehog Signaling

(4 January 2005)
Sci. STKE 2005 (265), tw6. [DOI: 10.1126/stke.2652005tw6]
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