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International Union of Basic and Clinical Pharmacology. LXXX. the Class Frizzled Receptors□S Supplemental Material can be found at: /content/suppl/2010/11/30/62.4.632.DC1.html 0031-6997/10/6204-632–667$20.00 PHARMACOLOGICAL REVIEWS Vol. 62, No. 4 Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics 2931/3636111 Pharmacol Rev 62:632–667, 2010 Printed in U.S.A. International Union of Basic and Clinical Pharmacology. LXXX. The Class Frizzled Receptors□S Gunnar Schulte Section of Receptor Biology and Signaling, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden Abstract............................................................................... 633 I. Introduction: the class Frizzled and recommended nomenclature............................ 633 II. Brief history of discovery and some phylogenetics ......................................... 634 III. Class Frizzled receptors ................................................................ 634 A. Frizzled and Smoothened structure ................................................... 635 1. The cysteine-rich domain ........................................................... 635 2. Transmembrane and intracellular domains........................................... 636 3. Motifs for post-translational modifications ........................................... 636 B. Class Frizzled receptors as PDZ ligands............................................... 637 C. Lipoglycoproteins as receptor ligands ................................................. 638 Downloaded from IV. Coreceptors............................................................................ 639 A. Extracellular matrix components ..................................................... 639 B. Low-density lipoprotein receptor-related protein 5/6 .................................... 639 C. Receptor tyrosine kinases as WNT receptors........................................... 639 D. Class Frizzled receptor dimerization .................................................. 640 V. Patched—the hedgehog receptor ......................................................... 640 by guest on October 2, 2021 VI. Non-WNT extracellular binding partners of Frizzleds...................................... 640 A. Soluble Frizzled-related proteins ..................................................... 640 B. Norrin ............................................................................. 641 C. Dickkopf ........................................................................... 641 D. R-spondin .......................................................................... 641 VII. WNT/Frizzled signaling paradigms ...................................................... 642 A. Molecular details: WNT/␤-catenin signaling ........................................... 642 B. A network approach: ␤-catenin-independent WNT/Frizzled signaling..................... 644 C. Planar cell polarity signaling ........................................................ 644 D. WNT/RAC and WNT/RHO ........................................................... 644 E. WNT/Ca2ϩ signaling ................................................................ 645 F. WNT/cAMP signaling ............................................................... 646 G. WNT/RAP signaling................................................................. 646 H. WNT/ROR signaling ................................................................ 646 VIII. Smoothened signaling .................................................................. 647 A. Regulation of Smoothened by Patched ................................................ 647 B. Transcriptional regulation via glioma-associated oncogene .............................. 648 C. The role of the primary cilium ....................................................... 648 IX. Frizzleds and Smoothened as G protein-coupled receptors .................................. 649 A. Pros and cons of G protein coupling .................................................. 649 B. Second messenger signaling ......................................................... 651 C. Kinetics of signaling ................................................................ 651 X. Class Frizzled receptor dynamics ........................................................ 652 A. Frizzled dynamics .................................................................. 652 Address correspondence to: Gunnar Schulte, Section of Receptor Biology & Signaling, Dept. Physiology & Pharmacology, Karolinska Institutet, S-171 77 Stockholm, Sweden. E-mail: [email protected] □S The online version of this article (available at http://pharmrev.aspetjournals.org) contains supplemental material. This article is available online at http://pharmrev.aspetjournals.org. doi:10.1124/pr.110.002931. 632 CLASS FRIZZLED— UNCONVENTIONAL GPCRS 633 B. Smoothened dynamics............................................................... 653 C. ␤-Arrestin.......................................................................... 653 XI. Mechanisms for signaling specificity ..................................................... 654 XII. Short overview of class Frizzled receptor function in physiology and disease ................. 655 XIII. Class Frizzled signaling as a pharmacological target....................................... 656 A. A pharmacologist’s view on Frizzled ligand binding modes .............................. 656 B. General considerations on “druggable” mechanisms .................................... 657 C. Frizzled-targeting drugs ............................................................. 658 D. Small-molecule compounds targeting Disheveled ....................................... 659 E. WNT and Frizzled antibodies ........................................................ 659 F. Recombinant Frizzled-cysteine-rich domains........................................... 660 G. Drugs targeting Hedgehog-Smoothened signaling ...................................... 660 XIV. Future directions ...................................................................... 660 Acknowledgments ...................................................................... 661 References ............................................................................ 661 Abstract——The receptor class Frizzled, which has role in embryonic patterning, physiology, cancer, and recently been categorized as a separate group of G other diseases. Despite intense efforts, many question protein-coupled receptors by the International Union marks and challenges remain in mapping receptor- of Basic and Clinical Pharmacology, consists of 10 ligand interaction, signaling routes, mechanisms of Frizzleds (FZD1–10) and Smoothened (SMO). The FZDs specificity and how these molecular details underlie are activated by secreted lipoglycoproteins of the disease and also the receptor’s important role in Wingless/Int-1 (WNT) family, whereas SMO is indi- physiology. This review therefore focuses on the mo- rectly activated by the Hedgehog (HH) family of pro- lecular aspects of WNT/FZD and HH/SMO signaling teins acting on the transmembrane protein Patched discussing receptor structure, mechanisms of signal (PTCH). Recent years have seen major advances in our transduction, accessory proteins, receptor dynam- knowledge about these seven-transmembrane-span- ics, and the possibility of targeting these signaling ning proteins, including: receptor function, molecular pathways pharmacologically. mechanisms of signal transduction, and the receptor’s I. Introduction: The Class Frizzled and protein-coupled receptor (GPCR) list as a separate fam- Recommended Nomenclature ily—the class Frizzled (Foord et al., 2005). In parallel, IUPHAR recommended a unifying Frizzled receptor no- The Frizzled family of seven-transmembrane-span- menclature for the mammalian receptors in which iso- ning receptors (7TMR1) and the closely related Smooth- form numbers are given as subscripts and Frizzled is ened (SMO) have been included in the International abbreviated FZD with capital letters, rather than previ- Union of Basic and Clinical Pharmacology (IUPHAR) G ously used names, such as Fz, Fzd, Frz, or Hfz. The class FZD includes 10 FZD isoforms in mammals; these are 1 Abbreviations: 7TMR, seven-transmembrane-spanning recep- denoted FZD . Smoothened, the eleventh member of tor; aa, amino acid(s); CHAPS, 3-[(3-cholamidopropyl)dimethylam- 1–10 monio]propanesulfonate; CK1, casein kinase 1; CRD, cysteine-rich the family, is abbreviated SMO. Nomenclature of FZDs domain; CREB, cAMP response element binding protein; DKK, Dick- in nonmammalian species, such as Caenorhabditis el- kopf; DOCK4, dedicator of cytokinesis 4; DVL, Disheveled; FJ9, egans, Drosophila melanogaster, and Xenopus laevis is ((2-(1-hydroxypentyl)-3-(2-phenylethyl)-6-methyl)indole-5-carboxylic handled independently (see Table 1), although a unify- acid; FZD, frizzled; GEF, guanine nucleotide exchange factor; GLI, ing terminology would be advantageous. Nomenclature glioma-associated oncogene; GPCR, G protein-coupled receptor; GRK, GPCR kinase; GSK3, glycogen synthase kinase 3; HEK, hu- for most mammalian GPCRs is based on the endogenous man embryonic kidney; HH, Hedgehog; IP3, inositol trisphosphate; ligand that binds and activates the cognate receptor. In IUPHAR, International Union of Basic and Clinical Pharmacology; the case of the class Frizzled receptors, however, the KRM, Kremen; LEF, lymphoid enhancer factor; LRP, low-density receptor names are derived from D. melanogaster phe- lipoprotein receptor-related protein; PCP, planar cell polarity; PDE, noptypes and associated gene
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