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src heterodimerically activates Lyn or Fyn to serve as targets for the diagnosis and treatment of esophageal squamous cell carcinoma

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Science China(Life Sciences) 2023年第6期66卷 1245-1263页

作者： Jing Zhang Di Zhao Lingyuan Zhang Yuanfan Xiao Qingnan Wu Yan Wang Jie Chen Qimin Zhan Key Laboratory of Carcinogenesis and Translational Research(Ministry of Education/Beijing) Laboratory of Molecular OncologyPeking University Cancer Hospital&InstituteBeijing100142China Peking University International Cancer Institute Peking UniversityBeijing100191China Research Unit of Molecular Cancer Research Chinese Academy of Medical SciencesBeijing100142China Institute of Cancer Research Shenzhen Bay LaboratoryShenzhen518107China

Although src is one of the oldest and most investigated oncoproteins,its function in tumor malignancy remains to be defined *** this study,we demonstrated that the inhibition of src activity by ponatinib effectively suppressed several malignant phenotypes of esophageal squamous cell carcinoma(ESCC)both in vitro and in vivo,whereas it did not produce growthinhibitory effects on normal esophageal epithelial cells(NEECs).Importantly,we combined phosphoproteomics and several cellular and molecular biologic strategies to identify that src interacted with the members of src-family kinases(SFKs),such as Fyn or Lyn,to form *** interactions with Fyn and Lyn phosphorylated the tyrosine sites in SH2(Fyn Tyr^(185)or Lyn Tyr^(183))and kinase domains(Fyn Tyr^(420) or Lyn Tyr^(397)),which critically contributed to ESCC *** contrast,src could not form heterodimers with Fyn or Lyn in *** used RNA sequencing to comprehensively demonstrate that the inhibition of src activity effectively blocked several critical tumor-promoting pathways,such as JAK/STAT,mTOR,stemness-related,and metabolism-related *** of the real-time polymerase chain reaction(RT-PCR)assay confirmed that Lyn and Fyn were critical effectors for the src-mediated expression of tumor growth or metastasis-related ***,results of the clinical ESCC samples showed that the hyperactivation of psrc Tyr^(419),Fyn Tyr^(185) or Tyr^(420),and Lyn Tyr^(183)or Tyr^(397)could be biomarkers of ESCC *** study illustrates that src/Fyn and src/Lyn heterodimers serve as targets for the treatment of ESCC.

关键词： esophageal squamous cell carcinoma heterodimer src-family kinase src tyrosine phosphorylation

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