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Kinome-wide siRNA screen identifies a DCLK2-TBK1 oncogenic signaling axis in clear cell renal cell carcinoma.
Hu, Lianxin; Zhang, Yanfeng; Guo, Lei; Zhong, Hua; Xie, Ling; Zhou, Jin; Liao, Chengheng; Yao, Hongwei; Fang, Jun; Liu, Hongyi; Zhang, Cheng; Zhang, Hui; Zhu, Xiaoqiang; Luo, Maowu; von Kriegsheim, Alex; Li, Bufan; Luo, Weibo; Zhang, Xuewu; Chen, Xian; Mendell, Joshua T; Xu, Lin; Kapur, Payal; Baldwin, Albert S; Brugarolas, James; Zhang, Qing.
Afiliación
  • Hu L; Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • Zhang Y; Quantitative Biomedical Research Center, Peter O'Donnell Jr. School of Public Health, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • Guo L; Quantitative Biomedical Research Center, Peter O'Donnell Jr. School of Public Health, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • Zhong H; Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Lyda Hill Department of Bioinformatics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • Xie L; Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC 27599, USA.
  • Zhou J; Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • Liao C; Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • Yao H; Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • Fang J; Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • Liu H; Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • Zhang C; Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • Zhang H; Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • Zhu X; Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • Luo M; Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • von Kriegsheim A; Cancer Research UK Scotland Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.
  • Li B; Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • Luo W; Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • Zhang X; Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • Chen X; Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC 27599, USA.
  • Mendell JT; Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern M
  • Xu L; Quantitative Biomedical Research Center, Peter O'Donnell Jr. School of Public Health, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • Kapur P; Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • Baldwin AS; Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
  • Brugarolas J; Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Internal Medicine, University of Texas Southw
  • Zhang Q; Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern M
Mol Cell ; 84(4): 776-790.e5, 2024 Feb 15.
Article en En | MEDLINE | ID: mdl-38211588
ABSTRACT
TANK-binding kinase 1 (TBK1) is a potential therapeutic target in multiple cancers, including clear cell renal cell carcinoma (ccRCC). However, targeting TBK1 in clinical practice is challenging. One approach to overcome this challenge would be to identify an upstream TBK1 regulator that could be targeted therapeutically in cancer specifically. In this study, we perform a kinome-wide small interfering RNA (siRNA) screen and identify doublecortin-like kinase 2 (DCLK2) as a TBK1 regulator in ccRCC. DCLK2 binds to and directly phosphorylates TBK1 on Ser172. Depletion of DCLK2 inhibits anchorage-independent colony growth and kidney tumorigenesis in orthotopic xenograft models. Conversely, overexpression of DCLK2203, a short isoform that predominates in ccRCC, promotes ccRCC cell growth and tumorigenesis in vivo. Mechanistically, DCLK2203 elicits its oncogenic signaling via TBK1 phosphorylation and activation. Taken together, these results suggest that DCLK2 is a TBK1 activator and potential therapeutic target for ccRCC.
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Carcinoma de Células Renales / Neoplasias Renales Límite: Humans Idioma: En Revista: Mol Cell Asunto de la revista: BIOLOGIA MOLECULAR Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Carcinoma de Células Renales / Neoplasias Renales Límite: Humans Idioma: En Revista: Mol Cell Asunto de la revista: BIOLOGIA MOLECULAR Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos