FER-mediated phosphorylation and PIK3R2 recruitment on IRS4 promotes AKT activation and tumorigenesis in ovarian cancer cells

Author:

Zhang Yanchun1ORCID,Xiong Xuexue1,Zhu Qi1,Zhang Jiali1,Chen Shengmiao1,Wang Yuetong1ORCID,Cao Jian2,Chen Li1,Hou Linjun1,Zhao Xi1,Hao Piliang1,Chen Jian3,Zhuang Min1,Li Dake2,Fan Gaofeng1ORCID

Affiliation:

1. School of Life Science and Technology, ShanghaiTech University

2. Department of Gynecology, Women’s Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital

3. ENT Institute and Department of Otorhinolaryngology, Eye & ENT Hospital, Fudan University

Abstract

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.

Funder

Ministry of Science and Technology of the People's Republic of China

National Natural Science Foundation of China

Science and Technology Commission of Shanghai Municipality

Shanghai Pujiang program

Shanghai Shuguang Program

ShanghaiTech University

Publisher

eLife Sciences Publications, Ltd

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

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