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Science 292 (5522): 1718-1722

Copyright © 2001 by the American Association for the Advancement of Science

G Protein Signaling from Activated Rat Frizzled-1 to the beta -Catenin-Lef-Tcf Pathway

Tong Liu,1 Anthony J. DeCostanzo,1 Xunxian Liu,1 Hsien-yu Wang,2 Sarah Hallagan,3 Randall T. Moon,3 Craig C. Malbon1*

The frizzled receptors, which mediate development and display seven hydrophobic, membrane-spanning segments, are cell membrane-localized. We constructed a chimeric receptor with the ligand-binding and transmembrane segments from the beta 2-adrenergic receptor (beta 2AR) and the cytoplasmic domains from rat Frizzled-1 (Rfz1). Stimulation of mouse F9 clones expressing the chimera (beta 2AR-Rfz1) with the beta -adrenergic agonist isoproterenol stimulated stabilization of beta -catenin, activation of a beta -catenin-sensitive promoter, and formation of primitive endoderm. The response was blocked by inactivation of pertussis toxin-sensitive, heterotrimeric guanine nucleotide-binding proteins (G proteins) and by depletion of Galpha q and Galpha o. Thus, G proteins are elements of Wnt/Frizzled-1 signaling to the beta -catenin-lymphoid-enhancer factor (LEF)-T cell factor (Tcf) pathway.

1 Department of Molecular Pharmacology and
2 Department of Physiology, Diabetes and Metabolic Diseases Research Center, University Medical Center, State University of New York at Stony Brook, Stony Brook, NY 11794-8651, USA.
3 Howard Hughes Medical Institute, Department of Pharmacology and Center for Developmental Biology, University of Washington School of Medicine, Seattle, WA 98195, USA.
*   To whom correspondence should be addressed. E-mail: craig{at}

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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
Wnt/Ca2+ signaling pathway: a brief overview.
A. De (2011)
Acta Biochim Biophys Sin 43, 745-756
   Abstract »    Full Text »    PDF »
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R. K. Bikkavilli and C. C. Malbon (2011)
J. Cell Sci. 124, 2310-2320
   Abstract »    Full Text »    PDF »
International Union of Basic and Clinical Pharmacology. LXXX. The Class Frizzled Receptors.
G. Schulte (2010)
Pharmacol. Rev. 62, 632-667
   Abstract »    Full Text »    PDF »
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N. Yokoyama, U. Golebiewska, H.-y. Wang, and C. C. Malbon (2010)
J. Cell Sci. 123, 3693-3702
   Abstract »    Full Text »    PDF »
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J. Neumann, K. Schaale, K. Farhat, T. Endermann, A. J. Ulmer, S. Ehlers, and N. Reiling (2010)
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   Abstract »    Full Text »    PDF »
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Y. R. Ji, M. O. Kim, S. H. Kim, D. H. Yu, M. J. Shin, H. J. Kim, H. S. Yuh, K. B. Bae, J. Y. Kim, H. D. Park, et al. (2010)
J. Biol. Chem. 285, 28627-28634
   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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T. P. Rao and M. Kuhl (2010)
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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S. Gardner, E. Stavrou, P. E Rischitor, E. Faccenda, and A. J Pawson (2010)
J. Mol. Endocrinol. 44, 195-201
   Abstract »    Full Text »    PDF »
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N. Yokoyama and C. C. Malbon (2009)
J. Cell Sci. 122, 4439-4451
   Abstract »    Full Text »    PDF »
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J. Cell Sci. 121, 3598-3607
   Abstract »    Full Text »    PDF »
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R. R. Wouda, M. R. K. S. Bansraj, A. W. M. de Jong, J. N. Noordermeer, and L. G. Fradkin (2008)
Development 135, 2277-2287
   Abstract »    Full Text »    PDF »
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H. A Kestler and M. Kuhl (2008)
Phil Trans R Soc B 363, 1333-1347
   Abstract »    Full Text »    PDF »
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H. Ge, J. Weiszmann, J. D. Reagan, J. Gupte, H. Baribault, T. Gyuris, J.-L. Chen, H. Tian, and Y. Li (2008)
J. Lipid Res. 49, 797-803
   Abstract »    Full Text »    PDF »
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R. K. Bikkavilli, M. E. Feigin, and C. C. Malbon (2008)
J. Cell Sci. 121, 234-245
   Abstract »    Full Text »    PDF »
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M. E. Feigin and C. C. Malbon (2007)
J. Cell Sci. 120, 3404-3414
   Abstract »    Full Text »    PDF »
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Y. Gao and H.-y. Wang (2007)
J. Biol. Chem. 282, 26490-26502
   Abstract »    Full Text »    PDF »
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A. Kikuchi and H. Yamamoto (2007)
J. Biochem. 141, 443-451
   Abstract »    Full Text »    PDF »
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N. Fujii, L. You, Z. Xu, K. Uematsu, J. Shan, B. He, I. Mikami, L. R. Edmondson, G. Neale, J. Zheng, et al. (2007)
Cancer Res. 67, 573-579
   Abstract »    Full Text »    PDF »
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A. R. Meloni, G. B. Fralish, P. Kelly, A. Salahpour, J. K. Chen, R. J. Wechsler-Reya, R. J. Lefkowitz, and M. G. Caron (2006)
Mol. Cell. Biol. 26, 7550-7560
   Abstract »    Full Text »    PDF »
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Y. Gao and H.-y. Wang (2006)
J. Biol. Chem. 281, 18394-18400
   Abstract »    Full Text »    PDF »
Phosphorylation of Frizzled-3.
W. A. Yanfeng, C. Tan, R. J. Fagan, and P. S. Klein (2006)
J. Biol. Chem. 281, 11603-11609
   Abstract »    Full Text »    PDF »
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J. Pharmacol. Exp. Ther. 317, 267-274
   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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F. Lin, D. S. Sepich, S. Chen, J. Topczewski, C. Yin, L. Solnica-Krezel, and H. Hamm (2005)
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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