Ixazomib enhances parathyroid hormone-induced β-catenin/T-cell factor signaling by dissociating β-catenin from the parathyroid hormone receptor.
Ixazomib enhances parathyroid hormone-induced β-catenin/T-cell factor signaling by dissociating β-catenin from the parathyroid hormone receptor.
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DOI：
10.1091/mbc.e17-02-0096
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发表时间：
2017-07-01
影响因子：
3.3
通讯作者：
Wang B
中科院分区：
文献类型：
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作者：
Yang Y;Lei H;Qiang YW;Wang B
蛋白酶体抑制剂 ixazomib (Izb) 将 β-catenin 从 PTH 受体上解离，通过 cAMP/PKA 信号通路增强 PTH 对 β-catenin/TCF 信号传导的刺激。这些发现为使用 Izb 作为 PTH 治疗骨质疏松症的辅助药物提供了理论依据。 PTH 在骨中的合成代谢作用主要由 cAMP/PKA 和不依赖 Wnt 的 β-连环蛋白/T 细胞因子 (TCF) 信号传导介导。 β-连环蛋白通过与 PTHR 结合，将 PTH 受体 (PTHR) 信号从 cAMP/PKA 激活切换为 PLC/PKC 激活。 Ixazomib (Izb) 最近被批准为第一个口服蛋白酶体抑制剂，用于治疗多发性骨髓瘤；它的部分作用是通过抑制病理性骨质破坏来发挥作用。据报道，蛋白酶体抑制剂可通过泛素-蛋白酶体途径稳定 β-连环蛋白。然而，Izb 如何影响 PTHR 激活以调节 β-catenin/TCF 信号转导尚不清楚。在本研究中，利用 CRISPR/Cas9 基因组编辑技术，我们发现 Izb 可以逆转 β-catenin 介导的 PTHR 信号开关，增强 PTH 诱导的成骨细胞中 cAMP 的生成和 cAMP 反应元件 - 荧光素酶的活性。 Izb 增加 β-连环蛋白的活性形式并促进 β-连环蛋白易位，从而将 β-连环蛋白从质膜上的 PTHR 解离。此外，Izb 促进 PTH 刺激的 GSK3β 磷酸化和 β-连环蛋白磷酸化。因此，Izb 通过 cAMP 依赖性激活增强 β-连环蛋白/TCF 信号转导的 PTH 刺激，这种作用是由于它将 β-连环蛋白与 PTHR 分开。这些发现提供了证据表明Izb可用于提高PTH治疗骨质疏松症和其他骨吸收疾病的疗效。
The proteasome inhibitor ixazomib (Izb) dissociates β-catenin from the PTH receptor to enhance PTH stimulation of β-catenin/TCF signaling through the cAMP/PKA signaling pathway. These findings provide a rationale for the use of Izb as an adjunct in the treatment of osteoporosis with PTH. 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 separating β-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.