Phosphorylation of IRS4 at YY111/112 promotes LUSC progression via PI3K/AKT pathway activation.

Yilixiati Aihemaiti, Qiuhan Ren, Xiangling Jiang, Kaideya Wushaying, Ran Chen, Yanli Wang, Xian Zhao, Lei Xu, Zhi Yang, Jianxiu Yu and 1 more

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Article in Oncogene, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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11 authors.

Yilixiati Aihemaiti *Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Qiuhan Ren *Department of Pharmaceutical and Artificial-Intelligence Sciences, Institute of Medical Artificial Intelligence, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Xiangling JiangDepartment of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Kaideya WushayingDepartment of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Ran ChenDepartment of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Yanli WangDepartment of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Xian ZhaoDepartment of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Lei XuDepartment of Biochemistry and Molecular Biology, Tongji University School of Medicine, Shanghai, China. xulei@tongji.edu.cn.

Zhi YangState Key Laboratory of Eye Health, Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. yangzhi@sibs.ac.cn.ORCID http://orcid.org/0000-0001-9440-7896

Jianxiu YuDepartment of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Jianxiu.Yu@gmail.com.ORCID http://orcid.org/0000-0002-6515-6001

Jian HuangDepartment of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, China. jyhuanj@shsmu.edu.cn.ORCID http://orcid.org/0000-0002-5033-9622

Funding

National Natural Science Foundation of China (National Science Foundation of China) 82073043National Natural Science Foundation of China (National Science Foundation of China) 82230100

6 · The paper itself

Abstract

Lung squamous cell carcinoma (LUSC) lacks effective targeted therapies despite frequent hyperactivation of the PI3K/AKT pathway, and the contribution of adaptor proteins to this process remains poorly defined. Here, we identify Insulin Receptor Substrate 4 (IRS4) as a common substrate of Src kinase and the phosphatase RPTPα, and uncover a previously unrecognized, conserved phosphorylation site at YY111/112 within the IRS4 PH domain. Src-mediated phosphorylation at this site is essential for IRS4-driven proliferation, anchorage-independent growth, and invasiveness in LUSC cells. Mechanistically, phosphorylation at YY111/112 induces conformational rearrangements in IRS4 that enhance the recruitment of the p85β SH2 domain to the YXXM motif of IRS4, thereby promoting AKT activation without altering IRS4 protein stability or subcellular distribution. An IRS4-derived cell-permeable phosphopeptide containing pYY111/112 disrupts the Src-IRS4 interaction and significantly suppresses tumor growth in vivo in a YY111/112-dependent manner. Consistently, YY111/112 phosphorylation is markedly elevated in human LUSC tissues and correlates with advanced disease stages. Collectively, these findings define a Src-IRS4-PI3K/AKT signaling axis and identify YY111/112 as a critical regulatory site of IRS4 and a potential therapeutic vulnerability in LUSC.

Identifiers

PMID42892654

DOI10.21105/joss.04200

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