Dual-specificity phosphatases (DUSPs) are defined by their capability to dephosphorylate both phosphoserine/phosphothreonine (pSer/pThr) and phosphotyrosine (pTyr). DUSP5, a member of DUSPs superfamily, is located in the nucleus and plays crucially regulatory roles in the signaling pathway transduction. In our present study, we discover that DUSP5 significantly promotes osteogenic differentiation of mesenchymal stromal cells (MSCs) by activating SMAD1 signaling pathway. Mechanistically, DUSP5 physically interacts with the phosphatase domain of small C-terminal phosphatase 1/2 (SCP1/2, SMAD1 phosphatases) by the linker region. In addition, we further confirm that DUSP5 activates SMAD1 signaling through a SCP1/2-dependent manner. Specifically, DUSP5 attenuates the SCP1/2-SMAD1 interaction by competitively binding to SCP1/2, which is responsible for the SMAD1 dephosphorylation, and thus results in the activation of SMAD1 signaling. Importantly, DUSP5 expression in mouse bone marrow MSCs is significantly reduced in ovariectomized (OVX) mice in which osteogenesis is highly passive, and overexpression of Dusp5 via tail vein injection reverses the bone loss of OVX mice efficiently. Collectively, this work demonstrates that the linker region of DUSP5 maybe a novel chemically modifiable target for controlling MSCs fate choices and for osteoporosis treatment.

中文翻译：

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DUSP5 通过 SMAD1 的 SCP1/2 依赖性磷酸化促进成骨分化

双特异性磷酸酶 (DUSP) 的定义是它们能够使磷酸丝氨酸/磷酸苏氨酸 (pSer/pThr) 和磷酸酪氨酸 (pTyr) 去磷酸化。DUSP5 是 DUSPs 超家族的成员，位于细胞核中，在信号通路转导中起着至关重要的调节作用。在我们目前的研究中，我们发现 DUSP5 通过激活 SMAD1 信号通路显着促进间充质基质细胞 (MSCs) 的成骨分化。从机制上讲，DUSP5 通过连接区域与小 C 末端磷酸酶 1/2（SCP1/2、SMAD1 磷酸酶）的磷酸酶结构域发生物理相互作用。此外，我们进一步证实 DUSP5 通过依赖 SCP1/2 的方式激活 SMAD1 信号。具体来说，DUSP5 通过与 SCP1/2 竞争性结合来减弱 SCP1/2-SMAD1 的相互作用，它负责 SMAD1 去磷酸化，从而导致 SMAD1 信号传导的激活。重要的是，在成骨高度被动的去卵巢（OVX）小鼠中，小鼠骨髓间充质干细胞中 DUSP5 的表达显着降低，而通过尾静脉注射Dusp5 可有效逆转 OVX 小鼠的骨质流失。总的来说，这项工作表明 DUSP5 的接头区域可能是一种新的化学修饰靶标，用于控制 MSCs 的命运选择和骨质疏松症的治疗。