IMR Press / FBL / Volume 9 / Issue 2 / DOI: 10.2741/1308

Frontiers in Bioscience-Landmark (FBL) is published by IMR Press from Volume 26 Issue 5 (2021). Previous articles were published by another publisher on a subscription basis, and they are hosted by IMR Press on imrpress.com as a courtesy and upon agreement with Frontiers in Bioscience.

Article
Frizzleds: new members of the superfamily of G-protein-coupled receptors
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1 Department of Pharmacology, School of Medicine, Health Sciences Center, State University of New York at Stony Brook, Stony Brook, New York 11794-8651, USA
Front. Biosci. (Landmark Ed) 2004, 9(2), 1048–1058; https://doi.org/10.2741/1308
Published: 1 May 2004
Abstract

The superfamily of membrane receptors that signal via heterotrimeric G-proteins includes more than 1500 members, classified into five basic groups, representing about 5-10% of the human genome. These G-protein-coupled receptors operate through a comparatively smaller group of heterotrimeric G-protein family of ∼20 members, each displaying an alpha subunit that binds and hydrolyzes GTP in combination with the beta-/gamma-subunit complex that is largely non-dissociable in vivo. Frizzleds represent the cell membrane receptors for a family of secreted glycoprotein ligands termed "Wnts" that play essential roles in development, including cell fate, adhesion, polarity, migration, and proliferation. Based upon a compelling set of experimental observations about the structure and downstream signaling of Wnt-Frizzled signaling, one can only conclude that Frizzleds are true members of the GPCR family and require heterotrimeric G-proteins to propagate signals from the Wnts to well-known effectors, including beta-catenin stabilization, mobilization of intracellular Ca2+, and activation of cyclic GMP phosphodiesterase. Careful study of primary structure of Frizzleds reveal heptihelical, 7-transmembrane segments, characteristic of GPCRs. Chimeric forms of Frizzleds, making use of the cytoplasmic domains of Frizzleds, substituted into the exofacial and transmembrane segments of the prototypic GPCR beta2-adrenergic receptor are functional and display the well-known GTP-shift in receptor affinity. Suppression of specific G-protein subunits suppress the ability of chimeric as well as authentic Frizzled-1 and Frizzled-2 to signal to their canonical pathways upon activation. The involvement of beta-arrestin, an important regulator of GPCR signaling, in Frizzled signaling is, therefore, not unexpected. Recognition of the GPCR character of Frizzled enables a more broad understanding of these receptors and of their mechanisms of downstream signaling.

Keywords
Frizzled
Heterotrimeric G-proteins
GProtein-Coupled Receptors
Cell Signaling
Frizzled-1
Frizzled-2
Review
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