Journal
CELLULAR SIGNALLING
Volume 25, Issue 6, Pages 1468-1475Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.cellsig.2013.03.009
Keywords
Frizzled; G protein; GPCR; Wnt signaling; Planar cell polarity; GDI
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Funding
- Edward J. Mallinkrodt, Jr. Foundation
- American Cancer Society [IRG-58-010-43]
- Culpeper Award
- Rockefeller Brothers Fund
- National Institutes of Health [GM63720-01]
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Frizzled receptors have long been thought to couple to G proteins but biochemical evidence supporting such an interaction has been lacking. Here we expressed mammalian Wnt-Frizzled fusion proteins in Saccharomyces cerevisiae and tested the receptors' ability to activate the yeast mitogen-activated protein kinase (MAPK) pathway via heterotrimeric G proteins. Our results show that Frizzled receptors can interact with G alpha(i), G alpha(q), and G alpha(s) proteins, thus confirming that Frizzled functions as a G protein coupled receptor (GPCR). However, the activity level of Frizzled-mediated G protein signaling was much lower than that of a typical GPCR and, surprisingly, was highest when coupled to G alpha(s). The Frizzled/G alpha(s) interaction was further established in vivo as Drosophila expressing a loss-of-function G alpha(s) allele rescued the photoreceptor differentiation phenotype of Frizzled mutant flies. Together, these data point to an important role for Frizzled as a nontraditional GPCR that preferentially couples to G alpha(s) heterotrimeric G proteins. (C) 2013 Elsevier Inc. All rights reserved.
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