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.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Adaptor Proteins, Signal Transducing / antagonists & inhibitors
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism*
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Animals
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Blotting, Western
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CHO Cells
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Cell Differentiation
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Cell Nucleus / metabolism
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Cricetinae
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Cricetulus
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Dishevelled Proteins
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Frizzled Receptors / genetics
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Frizzled Receptors / metabolism
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Humans
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Immunoprecipitation
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LDL-Receptor Related Proteins / genetics
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LDL-Receptor Related Proteins / metabolism
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Low Density Lipoprotein Receptor-Related Protein-5
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Low Density Lipoprotein Receptor-Related Protein-6
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Osteoclasts / cytology
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Osteoclasts / physiology*
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Osteogenesis
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Phosphoproteins / antagonists & inhibitors
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Phosphoproteins / genetics
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Phosphoproteins / metabolism*
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Phosphorylation
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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RNA, Small Interfering / pharmacology
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Receptor, Parathyroid Hormone, Type 1 / genetics
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Receptor, Parathyroid Hormone, Type 1 / metabolism*
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Receptors, G-Protein-Coupled
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Reverse Transcriptase Polymerase Chain Reaction
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Wnt Proteins / genetics
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Wnt Proteins / metabolism*
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beta Catenin / genetics
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beta Catenin / metabolism*
Substances
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Adaptor Proteins, Signal Transducing
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DVL2 protein, human
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Dishevelled Proteins
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FZD1 protein, human
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Frizzled Receptors
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LDL-Receptor Related Proteins
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LRP5 protein, human
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LRP6 protein, human
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Low Density Lipoprotein Receptor-Related Protein-5
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Low Density Lipoprotein Receptor-Related Protein-6
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PTH1R protein, human
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Phosphoproteins
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RNA, Messenger
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RNA, Small Interfering
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Receptor, Parathyroid Hormone, Type 1
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Receptors, G-Protein-Coupled
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Wnt Proteins
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beta Catenin