Parathyroid Hormone Receptor Directly Interacts with Dishevelled to Regulate Beta-Catenin Signaling and Osteoclastogenesis

Overview

Journal J Biol Chem

Specialty Biochemistry

Date 2010 Mar 10

PMID 20212039

Citations 48

Authors

Guillermo Romero

W Bruce Sneddon

Yanmei Yang

David Wheeler

Harry C Blair

Peter A Friedman

Affiliations

Soon will be listed here.

Abstract

Bone growth and remodeling depend upon the opposing rates of bone formation and resorption. These functions are regulated by intrinsic seven transmembrane-spanning receptors, the parathyroid hormone receptor (PTH1R) and frizzled (FZD), through their respective ligands, parathyroid hormone (PTH) and Wnt. FZD activation of canonical beta-catenin signaling requires the adapter protein Dishevelled (Dvl). We identified a Dvl-binding motif in the PTH1R. Here, we report that the PTH1R activates the beta-catenin pathway by directly recruiting Dvl, independent of Wnt or LRP5/6. PTH1R coimmunoprecipitated with Dvl. Deleting the carboxyl-terminal PTH1R PDZ-recognition domain did not abrogate PTH1R-Dvl interactions; nor did truncating the receptor at position 480. However, further deletion eliminating the putative Dvl recognition domain abolished PTH1R interactions with Dvl. PTH activated beta-catenin in a time- and concentration-dependent manner and translocated beta-catenin to the nucleus. beta-Catenin activation was inhibited by Dvl2 dominant negatives and by short hairpin RNA sequences targeted against Dvl2. PTH-induced osteoclastogenesis was also inhibited by Dvl2 dominant negative mutants. These findings demonstrate that G protein-coupled receptors other than FZD directly activate beta-catenin signaling, thereby mimicking many of the functions of the canonical Wnt-FZD pathway. The distinct modes whereby FZD and PTH1R activate beta-catenin control convergent or divergent effects on osteoblast differentiation, and osteoclastogenesis may arise from PTH1R-induced second messenger phosphorylation.

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References

Chen W, Hu L, Semenov M, Yanagawa S, Kikuchi A, Lefkowitz R . beta-Arrestin1 modulates lymphoid enhancer factor transcriptional activity through interaction with phosphorylated dishevelled proteins. Proc Natl Acad Sci U S A. 2001; 98(26):14889-94. PMC: 64954. DOI: 10.1073/pnas.211572798. View

Yao W, Cheng Z, Shahnazari M, Dai W, Johnson M, Lane N . Overexpression of secreted frizzled-related protein 1 inhibits bone formation and attenuates parathyroid hormone bone anabolic effects. J Bone Miner Res. 2009; 25(2):190-9. PMC: 3153380. DOI: 10.1359/jbmr.090719. View

Fu Q, Jilka R, Manolagas S, OBrien C . Parathyroid hormone stimulates receptor activator of NFkappa B ligand and inhibits osteoprotegerin expression via protein kinase A activation of cAMP-response element-binding protein. J Biol Chem. 2002; 277(50):48868-75. DOI: 10.1074/jbc.M208494200. View

Haq S, Michael A, Andreucci M, Bhattacharya K, Dotto P, Walters B . Stabilization of beta-catenin by a Wnt-independent mechanism regulates cardiomyocyte growth. Proc Natl Acad Sci U S A. 2003; 100(8):4610-5. PMC: 153603. DOI: 10.1073/pnas.0835895100. View

Sneddon W, Syme C, Bisello A, Magyar C, Rochdi M, Parent J . Activation-independent parathyroid hormone receptor internalization is regulated by NHERF1 (EBP50). J Biol Chem. 2003; 278(44):43787-96. DOI: 10.1074/jbc.M306019200. View

Wong H, Bourdelas A, Krauss A, Lee H, Shao Y, Wu D . Direct binding of the PDZ domain of Dishevelled to a conserved internal sequence in the C-terminal region of Frizzled. Mol Cell. 2003; 12(5):1251-60. PMC: 4381837. DOI: 10.1016/s1097-2765(03)00427-1. View

Malbon C . Frizzleds: new members of the superfamily of G-protein-coupled receptors. Front Biosci. 2004; 9:1048-58. DOI: 10.2741/1308. View

Hogarth D, Sandbo N, Taurin S, Kolenko V, Miano J, Dulin N . Dual role of PKA in phenotypic modulation of vascular smooth muscle cells by extracellular ATP. Am J Physiol Cell Physiol. 2004; 287(2):C449-56. DOI: 10.1152/ajpcell.00547.2003. View

London T, Lee H, Shao Y, Zheng J . Interaction between the internal motif KTXXXI of Idax and mDvl PDZ domain. Biochem Biophys Res Commun. 2004; 322(1):326-32. DOI: 10.1016/j.bbrc.2004.07.113. View

10.

Westendorf J, Kahler R, Schroeder T . Wnt signaling in osteoblasts and bone diseases. Gene. 2004; 341:19-39. DOI: 10.1016/j.gene.2004.06.044. View

11.

Chan S, Karpf D, Fowlkes M, Hooks M, Bradley M, Vuong V . Two homologs of the Drosophila polarity gene frizzled (fz) are widely expressed in mammalian tissues. J Biol Chem. 1992; 267(35):25202-7. View

12.

Lanske B, Karaplis A, Lee K, Luz A, Vortkamp A, PIRRO A . PTH/PTHrP receptor in early development and Indian hedgehog-regulated bone growth. Science. 1996; 273(5275):663-6. DOI: 10.1126/science.273.5275.663. View

13.

Songyang Z, Fanning A, Fu C, Xu J, Marfatia S, Chishti A . Recognition of unique carboxyl-terminal motifs by distinct PDZ domains. Science. 1997; 275(5296):73-7. DOI: 10.1126/science.275.5296.73. View

14.

Sokol S . Analysis of Dishevelled signalling pathways during Xenopus development. Curr Biol. 1996; 6(11):1456-67. DOI: 10.1016/s0960-9822(96)00750-6. View

15.

Korinek V, Barker N, Morin P, van Wichen D, de Weger R, Kinzler K . Constitutive transcriptional activation by a beta-catenin-Tcf complex in APC-/- colon carcinoma. Science. 1997; 275(5307):1784-7. DOI: 10.1126/science.275.5307.1784. View

16.

Wang S, Raab R, Schatz P, Guggino W, Li M . Peptide binding consensus of the NHE-RF-PDZ1 domain matches the C-terminal sequence of cystic fibrosis transmembrane conductance regulator (CFTR). FEBS Lett. 1998; 427(1):103-8. DOI: 10.1016/s0014-5793(98)00402-5. View

17.

Barnes M, Duckworth D, Beeley L . Frizzled proteins constitute a novel family of G protein-coupled receptors, most closely related to the secretin family. Trends Pharmacol Sci. 1998; 19(10):399-400. DOI: 10.1016/s0165-6147(98)01246-2. View

18.

Li J, Sarosi I, Yan X, Morony S, Capparelli C, Tan H . RANK is the intrinsic hematopoietic cell surface receptor that controls osteoclastogenesis and regulation of bone mass and calcium metabolism. Proc Natl Acad Sci U S A. 2000; 97(4):1566-71. PMC: 26475. DOI: 10.1073/pnas.97.4.1566. View

19.

Takemaru K, Moon R . The transcriptional coactivator CBP interacts with beta-catenin to activate gene expression. J Cell Biol. 2000; 149(2):249-54. PMC: 2175158. DOI: 10.1083/jcb.149.2.249. View

20.

Hecht A, Vleminckx K, Stemmler M, VAN Roy F, Kemler R . The p300/CBP acetyltransferases function as transcriptional coactivators of beta-catenin in vertebrates. EMBO J. 2000; 19(8):1839-50. PMC: 302022. DOI: 10.1093/emboj/19.8.1839. View