Src homology 2 domain-containing tyrosine phosphatase 2 (SHP2) is an essential tyrosine phosphatase that is pivotal in regulating various cellular signaling pathways such as cell growth, differentiation, and survival. The activation of SHP2 has been shown to have a therapeutic effect in colitis and Parkinson's disease. Thus, the identification of SHP2 activators and a complete understanding of their mechanism is required. We used a two-step screening assay to determine a novel allosteric activator of SHP2 that stabilizes it in an open conformation. Oleanolic acid was identified as a suitable candidate. By binding to R362, K364, and K366 in the active center of the PTP domain, oleanolic acid maintained the active open state of SHP2, which facilitated the binding between SHP2 and its substrate. This oleanolic acid-activated SHP2 hindered Th17 differentiation by disturbing the interaction between STAT3 and IL-6R and inhibiting the activation of STAT3. Furthermore, the activation of SHP2 and subsequent attenuation of the STAT3–Th17 axis, oleanolic acid effectively mitigated colitis in mice. This protective effect was abrogated by SHP2 knockout or administration of the SHP2 inhibitor SHP099. These findings underscore the potential of oleanolic acid as a promising therapeutic agent for treating inflammatory bowel diseases.

中文翻译：

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通过齐墩果酸变构激活 SHP2 抑制 STAT3-Th17 轴以改善结肠炎

含有 Src 同源 2 结构域的酪氨酸磷酸酶 2 (SHP2) 是一种必需的酪氨酸磷酸酶，在调节细胞生长、分化和存活等多种细胞信号传导途径中至关重要。 SHP2 的激活已被证明对结肠炎和帕金森病具有治疗作用。因此，需要鉴定 SHP2 激活剂并全面了解其机制。我们使用两步筛选测定法来确定 SHP2 的新型变构激活剂，该激活剂可将其稳定在开放构象中。齐墩果酸被确定为合适的候选者。通过与PTP结构域活性中心的R362、K364和K366结合，齐墩果酸维持SHP2的活性开放状态，从而促进SHP2与其底物之间的结合。这种齐墩果酸激活的 SHP2 通过干扰 STAT3 和 IL-6R 之间的相互作用并抑制 STAT3 的激活来阻碍 Th17 分化。此外，齐墩果酸激活 SHP2 并随后减弱 STAT3-Th17 轴，可有效减轻小鼠结肠炎。通过敲除 SHP2 或施用 SHP2 抑制剂 SHP099 可以消除这种保护作用。这些发现强调了齐墩果酸作为治疗炎症性肠病的有前途的治疗剂的潜力。