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    Parathyroid hormone receptor directly interacts with dishevelled to regulate beta-catenin signaling and osteoclastogenesis

    J Biol Chem. 2010 Mar 8. [Epub ahead of print]

    The authors find that PTH can directly modulate Wnt-beta-catenin signaling in osteoblastic cells through direct actions on the adapter protein Dishevelled.
    Authors: Romero G, Sneddon WB, Yang Y, et. al

    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, 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 C-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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