FER-mediated phosphorylation and PIK3R2 recruitment on IRS4 promotes AKT activation and tumorigenesis in ovarian cancer cells.
FER-mediated phosphorylation and PIK3R2 recruitment on IRS4 promotes AKT activation and tumorigenesis in ovarian cancer cells.
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FER 介导的 IRS4 磷酸化和 PIK3R2 募集促进卵巢癌细胞中 AKT 激活和肿瘤发生
DOI：
10.7554/elife.76183
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发表时间：
2022-05-12
期刊：
影响因子：
7.7
通讯作者：
Fan, Gaofeng
中科院分区：
文献类型：
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作者：
Zhang, Yanchun;Xiong, Xuexue;Zhu, Qi;Zhang, Jiali;Chen, Shengmiao;Wang, Yuetong;Cao, Jian;Chen, Li;Hou, Linjun;Zhao, Xi;Hao, Piliang;Chen, Jian;Zhuang, Min;Li, Dake;Fan, Gaofeng
酪氨酸磷酸化由酪氨酸激酶和磷酸酶调控，以时间和空间依赖的方式调节多层信号网络。这种翻译后修饰的失调不可避免地与病理疾病有关。我们以前的工作已经证明，非受体酪氨酸激酶FER在卵巢癌中上调，从而抑制转移表型。然而，由于卵巢癌的已知底物数量有限，其促增殖活性的分子基础仍然是个谜。在这里，我们使用质谱仪和生化方法来确定胰岛素受体底物4(Irs4)是一种新的FER底物。FER使其激活域与IRS4的PH和PTB结构域结合。在卵巢癌OVCAR-5细胞中使用基于邻近标记系统，我们确定FER介导的Tyr779的磷酸化使Irs4能够招募PI3K的调节亚基PIK3R2/P85β，并激活PI3K-AKT通路。用磷酸化缺陷突变体挽救Irs4缺失的卵巢肿瘤细胞，而不是WT Irs4，在体外和体内都延迟了卵巢肿瘤细胞的增殖。总体而言，我们揭示了FER和IRS4之间的一种激酶-底物模式，药物抑制FER激酶可能有利于PI3K-AKT过度激活的卵巢癌患者。
Tyrosine phosphorylation, orchestrated by tyrosine kinases and phosphatases, modulates a multi-layered signaling network in a time- and space-dependent manner. Dysregulation of this post-translational modification is inevitably associated with pathological diseases. Our previous work has demonstrated that non-receptor tyrosine kinase FER is upregulated in ovarian cancer, knocking down which attenuates metastatic phenotypes. However, due to the limited number of known substrates in the ovarian cancer context, the molecular basis for its pro-proliferation activity remains enigmatic. Here, we employed mass spectrometry and biochemical approaches to identify insulin receptor substrate 4 (IRS4) as a novel substrate of FER. FER engaged its kinase domain to associate with the PH and PTB domains of IRS4. Using a proximity-based tagging system in ovarian carcinoma-derived OVCAR-5 cells, we determined that FER-mediated phosphorylation of Tyr779 enables IRS4 to recruit PIK3R2/p85β, the regulatory subunit of PI3K, and activate the PI3K-AKT pathway. Rescuing IRS4-null ovarian tumor cells with phosphorylation-defective mutant, but not WT IRS4 delayed ovarian tumor cell proliferation both in vitro and in vivo. Overall, we revealed a kinase-substrate mode between FER and IRS4, and the pharmacological inhibition of FER kinase may be beneficial for ovarian cancer patients with PI3K-AKT hyperactivation.
影响因子：
--
作者：
Hellwig S;Miduturu CV;Kanda S;Zhang J;Filippakopoulos P;Salah E;Deng X;Choi HG;Zhou W;Hur W;Knapp S;Gray NS;Smithgall TE
通讯作者：
Smithgall TE
影响因子：
3.7
作者：
Xu YZ;Thuraisingam T;Kanagaratham C;Tao S;Radzioch D
通讯作者：
Radzioch D