Type Size

    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.

    Full Text

This site uses cookies. By continuing to browse the site you are agreeing to our use of cookies. Review our Policies and Procedures for more details