國家衛生研究院 NHRI:Item 3990099045/15381
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    題名: Intervention of AXL in EGFR signaling via phosphorylation and stabilization of MIG6 in non-small cell Lung cancer
    作者: Yang, YY;Lin, SC;Lay, JD;Cho, CY;Jang, T;Ku, HY;Yao, CJ;Chuang, SE
    貢獻者: National Institute of Cancer Research
    摘要: About 80% of lung cancer patients are diagnosed with non-small cell lung cancer (NSCLC). EGFR mutation and overexpression are common in NSCLC, thus making EGFR signaling a key target for therapy. While EGFR kinase inhibitors (EGFR-TKIs) are widely used and efficacious in treatment, increases in resistance and tumor recurrence with alternative survival pathway activation, such as that of AXL and MET, occur frequently. AXL is one of the EMT (epithelial-mesenchymal transition) signature genes, and EMT morphological changes are also responsible for EGFR-TKI resistance. MIG6 is a negative regulator of ERBB signaling and has been reported to be positively correlated with EGFR-TKI resistance, and downregulation of MIG6 by miR-200 enhances EMT transition. While MIG6 and AXL are both correlated with EMT and EGFR signaling pathways, how AXL, MIG6 and EGFR interplay in lung cancer remains elusive. Correlations between AXL and MIG6 expression were analyzed using Oncomine or the CCLE. A luciferase reporter assay was used for determining MIG6 promoter activity. Ectopic overexpression, RNA interference, Western blot analysis, qRT-PCR, a proximity ligation assay and a coimmunoprecipitation assay were performed to analyze the effects of certain gene expressions on protein-protein interaction and to explore the underlying mechanisms. An in vitro kinase assay and LC-MS/MS were utilized to determine the phosphorylation sites of AXL. In this study, we demonstrate that MIG6 is a novel substrate of AXL and is stabilized upon phosphorylation at Y310 and Y394/395 by AXL. This study reveals a connection between MIG6 and AXL in lung cancer. AXL phosphorylates and stabilizes MIG6 protein, and in this way EGFR signaling may be modulated. This study may provide new insights into the EGFR regulatory network and may help to advance cancer treatment.
    日期: 2023-10-04
    關聯: International Journal of Molecular Sciences. 2023 Oct 04;24(19):Article number 14879.
    Link to: http://dx.doi.org/10.3390/ijms241914879
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=1661-6596&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:001083230100001
    Cited Times(Scopus): https://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=85174727070
    顯示於類別:[莊雙恩] 期刊論文

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