{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T03:36:59Z","timestamp":1790221019197,"version":"4.1.0"},"reference-count":53,"publisher":"American Society for Cell Biology (ASCB)","issue":"13","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["MBoC"],"published-print":{"date-parts":[[2017,7]]},"abstract":"<jats:p>The anabolic action of PTH in bone is mostly mediated by cAMP\/PKA and Wnt-independent activation of \u03b2-catenin\/T-cell factor (TCF) signaling. \u03b2-Catenin switches the PTH receptor (PTHR) signaling from cAMP\/PKA to PLC\/PKC activation by binding to the PTHR. Ixazomib (Izb) was recently approved as the first orally administered proteasome inhibitor for the treatment of multiple myeloma; it acts in part by inhibition of pathological bone destruction. Proteasome inhibitors were reported to stabilize \u03b2-catenin by the ubiquitin-proteasome pathway. However, how Izb affects PTHR activation to regulate \u03b2-catenin\/TCF signaling is poorly understood. In the present study, using CRISPR\/Cas9 genome-editing technology, we show that Izb reverses \u03b2-catenin\u2013mediated PTHR signaling switch and enhances PTH-induced cAMP generation and cAMP response element\u2013luciferase activity in osteoblasts. Izb increases active forms of \u03b2-catenin and promotes \u03b2-catenin translocation, thereby dissociating \u03b2-catenin from the PTHR at the plasma membrane. Furthermore, Izb facilitates PTH-stimulated GSK3\u03b2 phosphorylation and \u03b2-catenin phosphorylation. Thus Izb enhances PTH stimulation of \u03b2-catenin\/TCF signaling via cAMP-dependent activation, and this effect is due to its separating \u03b2-catenin from the PTHR. These findings provide evidence that Izb may be used to improve the therapeutic efficacy of PTH for the treatment of osteoporosis and other resorptive bone diseases.<\/jats:p>","DOI":"10.1091\/mbc.e17-02-0096","type":"journal-article","created":{"date-parts":[[2017,5,12]],"date-time":"2017-05-12T00:40:19Z","timestamp":1494549619000},"page":"1792-1803","source":"Crossref","is-referenced-by-count":15,"title":["Ixazomib enhances parathyroid hormone\u2013induced \u03b2-catenin\/T-cell factor signaling by dissociating \u03b2-catenin from the parathyroid hormone receptor"],"prefix":"10.1091","volume":"28","author":[{"given":"Yanmei","family":"Yang","sequence":"first","affiliation":[{"name":"Center for Translational Medicine, Department of Medicine, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA 19107"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Lei","sequence":"additional","affiliation":[{"name":"Center for Translational 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