Ixazomib enhances parathyroid hormone-induced β-catenin/T-cell factor signaling by dissociating β-catenin from the parathyroid hormone receptor

Molecular Biology of the Cell
Yanmei YangBin Wang

Abstract

The anabolic action of PTH in bone is mostly mediated by cAMP/PKA and Wnt-independent activation of β-catenin/T-cell factor (TCF) signaling. β-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 β-catenin by the ubiquitin-proteasome pathway. However, how Izb affects PTHR activation to regulate β-catenin/TCF signaling is poorly understood. In the present study, using CRISPR/Cas9 genome-editing technology, we show that Izb reverses β-catenin-mediated PTHR signaling switch and enhances PTH-induced cAMP generation and cAMP response element-luciferase activity in osteoblasts. Izb increases active forms of β-catenin and promotes β-catenin translocation, thereby dissociating β-catenin from the PTHR at the plasma membrane. Furthermore, Izb facilitates PTH-stimulated GSK3β phosphorylation and β-catenin phosphorylation. Thus Izb enhances PTH stimulation of β-catenin/TCF signaling via cAMP-dependent activation, and this effect is due to its s...Continue Reading

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Citations

Oct 19, 2017·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Tonio PeraRaymond B Penn
Jun 9, 2019·Journal of Experimental & Clinical Cancer Research : CR·Honghong ShenChen Wang
Jan 30, 2019·Scientific Reports·Kenichiro IioYutaka Ando
Aug 29, 2018·International Journal of Endocrinology·Yanmei Yang, Bin Wang

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Methods Mentioned

BETA
nuclear translocation
pull-down
confocal microscopy
coIP
immunoprecipitation assay
transfection

Software Mentioned

Prism
Evos
GraphPad

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