在结直肠癌中，干细胞因子（SCF）以糖原合成酶激酶3β（GSK3β）依赖的方式靶向降解朱巴蛋白（Ajuba）。
SCF targets Ajuba for degradation in a GSK3β-dependent manner in colorectal cancer.
作者信息
Li Liangshan, Zhu Feng, Liang Yupei, Chen Yuanyuan, Pan Yongfu, Jia Lijun, Wang Shiwen, Zhao Hu
机构信息
Department of Laboratory Medicine, Huadong Hospital, Fudan University, Shanghai, 200040, China; Cancer Institute, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China.
Cancer Institute, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China.
出版信息
Neoplasia. 2025 May 13;66:101175. doi: 10.1016/j.neo.2025.101175.
Ajuba (ajuba LIM protein, JUB) is a member of the Ajuba family, and its oncogenic biological functions in colorectal cancer (CRC) have been extensively reported including proliferation, metastasis and resistance to chemotherapy. Although considerable studies have reported the regulation of Ajuba at the transcriptional level, the potential mechanisms of regulating Ajuba protein stability have not been fully elucidated to date. Herein, we showed that the mRNA and protein expression of Ajuba is upregulated in CRC tissues, high protein level correlates with unfavorable prognosis. Importantly, we identified Ajuba as a novel substrate of GSK3β kinase and SCF E3 ubiquitin ligase. Mechanistically, GSK3β phosphorylates Ajuba at serine 163 in the highly conserved degron motif (TSGIS), which determines the interaction between Ajuba and the C-terminal WD40 domain of β-TrCP, and subsequent ubiquitination and targeted proteasomal degradation of Ajuba by β-TrCP. Conversely, the S163A mutant significantly attenuates the ubiquitination level of Ajuba. Overall, our study reveals a novel regulatory mechanism of Ajuba at post-translational level and sheds light on the role of GSK3β-β-TrCP axis in the turnover of Ajuba in CRC.
Ajuba（Ajuba LIM蛋白，JUB）是Ajuba家族的成员，其在结直肠癌（CRC）中的致癌生物学功能已有大量报道，包括增殖、转移和化疗耐药性。尽管有大量研究报道了Ajuba在转录水平的调控，但迄今为止，Ajuba蛋白稳定性的潜在调控机制尚未完全阐明。在此，我们发现Ajuba在CRC组织中的mRNA和蛋白表达上调，高蛋白水平与不良预后相关。重要的是，我们确定Ajuba是GSK3β激酶和SCF E3泛素连接酶的新底物。机制上，GSK3β在高度保守的降解基序（TSGIS）中的丝氨酸163处磷酸化Ajuba，这决定了Ajuba与β-TrCP的C末端WD40结构域之间的相互作用，随后β-TrCP对Ajuba进行泛素化和靶向蛋白酶体降解。相反，S163A突变体显著降低了Ajuba的泛素化水平。总体而言，我们的研究揭示了Ajuba在翻译后水平上的一种新调控机制，并阐明了GSK3β-β-TrCP轴在CRC中Ajuba周转中的作用。
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