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Vol. 19, Issue 12, 5478-5489, December 2008

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Smoothened Signaling in Vertebrates Is Facilitated by a G Protein-coupled Receptor Kinase

Melanie Philipp^*,,, Gregory B. Fralish^*,, Alison R. Meloni^*, Wei Chen, Alyson W. MacInnes^*,||, Lawrence S. Barak^*, and Marc G. Caron^*

*Departments of Cell Biology, Medicine, and Neurobiology, Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, NC 27710; and Institute of Experimental and Clinical Pharmacology, University of Freiburg, Germany

Submitted May 2, 2008; Revised August 29, 2008; Accepted September 17, 2008
Monitoring Editor: Marianne Bronner-Fraser

Smoothened, a heptahelical membrane protein, functions as the transducer of Hedgehog signaling. The kinases that modulate Smoothened have been thoroughly analyzed in flies. However, little is known about how phosphorylation affects Smoothened in vertebrates, mainly, because the residues, where Smoothened is phosphorylated are not conserved from Drosophila to vertebrates. Given its molecular architecture, Smoothened signaling is likely to be regulated in a manner analogous to G protein–coupled receptors (GPCRs). Previously, it has been shown, that arrestins and GPCR kinases, (GRKs) not only desensitize G protein–dependent receptor signaling but also function as triggers for GPCR trafficking and formation of signaling complexes. Here we describe that a GRK contributes to Smoothened-mediated signaling in vertebrates. Knockdown of the zebrafish homolog of mammalian GRK2/3 results in lowered Hedgehog transcriptional responses, impaired muscle development, and neural patterning. Results obtained in zebrafish are corroborated both in cell culture, where zGRK2/3 phosphorylates Smoothened and promotes Smoothened signal transduction and in mice where deletion of GRK2 interferes with neural tube patterning. Together, these data suggest that a GRK functions as a vertebrate kinase for Smoothened, promoting Hedgehog signal transduction during early development.

These authors contributed equally to this work.

^|| Present address: Hubrecht Institute, 3584 CT Utrecht, The Netherlands.

Address correspondence to: Marc G. Caron (caron002{at}mc.duke.edu).

Abbreviations used: barr, β-arrestin; GPCR, G protein–coupled receptor; GRK, G protein–coupled receptor kinase; Hh, Hedgehog; Ptc-1, Patched-1; Smo, Smoothened; 7TMR, 7-transmembrane spanning receptor.

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