Department of Immunology, School of Medicine, Keimyung University, Daegu, 42601, South Korea.
Center for Forensic Pharmaceutical Science, Keimyung University, Daegu, 42601, South Korea.
Cell Death Dis. 2023 Jun 17;14(6):366. doi: 10.1038/s41419-023-05884-z.
The Raptor signaling pathway is a critical point of intervention in the invasion and progression of cancer. The non-receptor tyrosine kinase Src-mediated phosphorylation of OTUB1-Y26 plays a critical role in Raptor stabilization, whereas cathepsin K inhibitor (odanacatib; ODN) and knockdown (siRNA) induce Raptor destabilization. However, the mechanisms involved in cathepsin K inhibition-induced OTUB1-Y26 phosphorylation in Raptor stabilization have not been yet elucidated. This study showed that cathepsin K inhibition activates SHP2, a tyrosine phosphatase, that dephosphorylates OTUB1 and destabilizes Raptor, whereas SHP2 deletion and pharmacological inhibition increase OTUB1-Y26 phosphorylation and Raptor expression. SHP2 deletion also led to the inhibition of ODN-induced mitochondrial ROS, fusion, and dysfunction. Furthermore, cathepsin K inhibition phosphorylated spleen tyrosine kinase (Syk) at Y525 and Y526, resulting in the SHP2-mediated dephosphorylation of OTUB1-Y26. Collectively, our findings identified Syk not only as an upstream tyrosine kinase required for SHP2 activation but also showed a critical mechanism that regulates ODN-induced Raptor downregulation and mitochondrial dysfunction. In conclusion, Syk/SHP2/Src/OTUB1 axis-mediated signaling can act as a therapeutic target in cancer management.
Raptor 信号通路是癌症侵袭和进展干预的关键点。非受体酪氨酸激酶Src 介导的 OTUB1-Y26 磷酸化在 Raptor 稳定中起着关键作用，而组织蛋白酶 K 抑制剂（odanacatib；ODN）和敲低（siRNA）诱导 Raptor 失稳。然而，组织蛋白酶 K 抑制诱导 Raptor 稳定中 OTUB1-Y26 磷酸化的机制尚未阐明。本研究表明，组织蛋白酶 K 抑制激活了酪氨酸磷酸酶 SHP2，其去磷酸化 OTUB1 并使 Raptor 失稳，而 SHP2 缺失和药理学抑制增加了 OTUB1-Y26 磷酸化和 Raptor 表达。SHP2 缺失还导致 ODN 诱导的线粒体 ROS、融合和功能障碍的抑制。此外，组织蛋白酶 K 抑制使脾酪氨酸激酶 (Syk) 在 Y525 和 Y526 处磷酸化，导致 SHP2 介导的 OTUB1-Y26 去磷酸化。总之，我们的研究结果不仅确定了 Syk 作为激活 SHP2 所需的上游酪氨酸激酶，还表明了一种关键机制，可调节 ODN 诱导的 Raptor 下调和线粒体功能障碍。总之，Syk/SHP2/Src/OTUB1 轴介导的信号转导可作为癌症管理的治疗靶点。
