Kinome-wide siRNA screen identifies a DCLK2-TBK1 oncogenic signaling axis in clear cell renal cell carcinoma

被引：2

作者：

Hu, Lianxin ^{[1
]}

Zhang, Yanfeng ^{[2
]}

Guo, Lei ^{[2
]}

Zhong, Hua ^{[1
,3
]}

Xie, Ling ^{[4
]}

Zhou, Jin ^{[1
]}

Liao, Chengheng ^{[1
]}

Yao, Hongwei ^{[1
]}

Fang, Jun ^{[1
]}

Liu, Hongyi ^{[1
]}

Zhang, Cheng ^{[1
]}

Zhang, Hui ^{[5
]}

Zhu, Xiaoqiang ^{[6
]}

Luo, Maowu ^{[1
]}

von Kriegsheim, Alex ^{[7
]}

Li, Bufan ^{[8
,9
]}

Luo, Weibo ^{[1
,5
]}

Zhang, Xuewu ^{[5
,9
]}

Chen, Xian ^{[4
]}

Mendell, Joshua T. ^{[6
,10
,11
,12
]}

Xu, Lin ^{[2
]}

Kapur, Payal ^{[13
]}

Baldwin, Albert S. ^{[14
]}

Brugarolas, Jame ^{[10
,13
,15
]}

Zhang, Qing ^{[1
,10
,13
]}

机构：

[1] Univ Texas Southwestern Med Ctr, Dept Pathol, Dallas, TX 75390 USA

[2] Univ Texas Southwestern Med Ctr, Quantitat Biomed Res Ctr, Peter ODonnell Jr Sch Publ Hlth, Dallas, TX 75390 USA

[3] Univ Texas Southwestern Med Ctr, Lyda Hill Dept Bioinformat, Dallas, TX 75390 USA

[4] Univ N Carolina, Dept Biochem & Biophys, Chapel Hill, NC 27599 USA

[5] Univ Texas Southwestern Med Ctr, Dept Pharmacol, Dallas, TX 75390 USA

[6] Univ Texas Southwestern Med Ctr, Dept Mol Biol, Dallas, TX 75390 USA

[7] Univ Edinburgh, Inst Genet & Canc, Canc Res UK Scotland Ctr, Edinburgh, Scotland

[8] Univ Texas Southwestern Med Ctr, Dept Physiol, Dallas, TX 75390 USA

[9] Univ Texas Southwestern Med Ctr, Dept Biophys, Dallas, TX 75390 USA

[10] Univ Texas Southwestern Med Ctr, Simmons Comprehens Canc Ctr, Dallas, TX 75390 USA

[11] Univ Texas Southwestern Med Ctr, Hamon Ctr Regenerat Sci & Med, Dallas, TX 75390 USA

[12] Univ Texas Southwestern Med Ctr, Howard Hughes Med Inst, Dallas, TX 75390 USA

[13] Univ Texas Southwestern Med Ctr, Simmons Comprehens Canc Ctr, Kidney Canc Program, Dallas, TX 75390 USA

[14] Univ N Carolina, Lineberger Comprehens Canc Ctr, Sch Med, Chapel Hill, NC 27599 USA

[15] Univ Texas Southwestern Med Ctr, Dept Internal Med, Dallas, TX 75390 USA

来源：

MOLECULAR CELL | 2024年 / 84卷 / 04期

关键词：

DOUBLECORTIN-LIKE-KINASE; HIF-ALPHA; NEURONAL MIGRATION; CATALYTIC DOMAIN; PROTEIN-KINASES; TBK1; TUMOR; TARGET; CANCER; DCLK1;

D O I：

10.1016/j.molcel.2023.12.010

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：776 / 790.e5

页数：21

共 50 条

[1] Kinome-wide siRNA screening identifies DCLK2 as a TBK1 activator and therapeutic target for ccRCC
Hu, Lianxin
Zhang, Qing
CANCER RESEARCH, 2023, 83 (16)
[2] BBOX1 restrains TBK1-mTORC1 oncogenic signaling in clear cell renal cell carcinoma
Liao, Chengheng
Hu, Lianxin
Jia, Liwei
Zhou, Jin
Wang, Tao
Kim, Kangsan
Zhong, Hua
Yao, Hongwei
Dong, Lei
Guo, Lei
Liang, Qian
Zhang, Cheng
Zhao, Fangzhou
Fang, Jun
Liu, Hongyi
Li, Shina
Xu, Lin
Simon, Jeremy M.
Malladi, Srinivas
Kapur, Payal
Brugarolas, James
Deberardinis, Ralph J.
Zhang, Qing
NATURE COMMUNICATIONS, 2025, 16 (01)
[3] A kinome-wide high-content siRNA screen identifies MEK5-ERK5 signaling as critical for breast cancer cell EMT and metastasis
Pavan, Simona
Meyer-Schaller, Nathalie
Diepenbruck, Maren
Kalathur, Ravi Kiran Reddy
Saxena, Meera
Christofori, Gerhard
ONCOGENE, 2018, 37 (31) : 4197 - 4213
[4] A kinome-wide screen identifies a CDKL5-SOX9 regulatory axis in epithelial cell death and kidney injury
Kim, Ji Young
Bai, Yuntao
Jayne, Laura A.
Hector, Ralph D.
Persaud, Avinash K.
Ong, Su Sien
Rojesh, Shreshtha
Raj, Radhika
Feng, Mei Ji He Ho
Chung, Sangwoon
Cianciolo, Rachel E.
Christman, John W.
Campbell, Moray J.
Gardner, David S.
Baker, Sharyn D.
Sparreboom, Alex
Govindarajan, Rajgopal
Singh, Harpreet
Chen, Taosheng
Poi, Ming
Susztak, Katalin
Cobb, Stuart R.
Pabla, Navjot Singh
NATURE COMMUNICATIONS, 2020, 11 (01)
[5] A kinome-wide screen identifies a CDKL5-SOX9 regulatory axis in epithelial cell death and kidney injury
Ji Young Kim
Yuntao Bai
Laura A. Jayne
Ralph D. Hector
Avinash K. Persaud
Su Sien Ong
Shreshtha Rojesh
Radhika Raj
Mei Ji He Ho Feng
Sangwoon Chung
Rachel E. Cianciolo
John W. Christman
Moray J. Campbell
David S. Gardner
Sharyn D. Baker
Alex Sparreboom
Rajgopal Govindarajan
Harpreet Singh
Taosheng Chen
Ming Poi
Katalin Susztak
Stuart R. Cobb
Navjot Singh Pabla
Nature Communications, 11
[6] A kinome-wide high-content siRNA screen identifies MEK5–ERK5 signaling as critical for breast cancer cell EMT and metastasis
Simona Pavan
Nathalie Meyer-Schaller
Maren Diepenbruck
Ravi Kiran Reddy Kalathur
Meera Saxena
Gerhard Christofori
Oncogene, 2018, 37 : 4197 - 4213
[7] Kinome expression profiling identifies IKBKE as a predictor of overall survival in clear cell renal cell carcinoma patients
Hildebrandt, Michelle A. T.
Tan, Weiqi
Tamboli, Pheroze
Huang, Maosheng
Ye, Yuanqing
Lin, Jie
Lee, Ju-Seog
Wood, Christopher G.
Wu, Xifeng
CARCINOGENESIS, 2012, 33 (04) : 799 - 803
[8] The Oncogenic Role of COL23A1 in Clear Cell Renal Cell Carcinoma
Fujiang Xu
Kun Chang
Jian Ma
Yuanyuan Qu
Huyang Xie
Bo Dai
Hualei Gan
Hailiang Zhang
Guohai Shi
Yao Zhu
Yiping Zhu
Yijun Shen
Dingwei Ye
Scientific Reports, 7
[9] The Oncogenic Role of COL23A1 in Clear Cell Renal Cell Carcinoma
Xu, Fujiang
Chang, Kun
Ma, Jian
Qu, Yuanyuan
Xie, Huyang
Dai, Bo
Gan, Hualei
Zhang, Hailiang
Shi, Guohai
Zhu, Yao
Zhu, Yiping
Shen, Yijun
Ye, Dingwei
SCIENTIFIC REPORTS, 2017, 7
[10] VHL loss of function and its impact on oncogenic signaling networks in clear cell renal cell carcinoma
Linehan, W. Marston
Rubin, Jeffrey S.
Bottaro, Donald P.
INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY, 2009, 41 (04): : 753 - 756

← 1 2 3 4 5 →