RETRACTED: The receptor tyrosine kinase AXL mediates nuclear translocation of the epidermal growth factor receptor.
RETRACTED: The receptor tyrosine kinase AXL mediates nuclear translocation of the epidermal growth factor receptor.
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DOI：
10.1126/scisignal.aag1064
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发表时间：
2017-01-03
影响因子：
7.3
通讯作者：
Wheeler DL
中科院分区：
文献类型：
--
作者：
Brand TM;Iida M;Corrigan KL;Braverman CM;Coan JP;Flanigan BG;Stein AP;Salgia R;Rolff J;Kimple RJ;Wheeler DL
表皮生长因子受体(EGFR)是各种癌症患者的治疗靶点。不幸的是，对EGFR靶向治疗的耐药性很常见。以往的研究证实了EGFR单抗西妥昔单抗耐药的两种机制：一是EGFR的核转位绕过西妥昔单抗的抑制作用；二是受体酪氨酸激酶Ax1通过维持EGFR激活和下游信号转导来介导西妥昔单抗抵抗。因此，我们假设Axl在西妥昔单抗耐药的背景下介导了EGFR的核转位。在培养的非小细胞肺癌和患者来源的小鼠异种移植中，西妥昔单抗耐药克隆增加了Ax1和核EGFR(NEGFR)的丰度。细胞分裂分析、超分辨显微镜和电子显微镜显示AXL基因缺失减少了nEGFR的积累。SRC家族激酶(SFK)及其家族配体促进EGFR的核转位。我们发现，Ax1基因敲除降低了编码SFK家族成员YES和LYN的基因以及配体NeuRegin-1(NRG1)的表达。AXL基因敲除也减少了EGFR与相关受体HER3的相互作用和HER3在细胞核内的积聚。在缺乏Axl的细胞中过表达Lyn和NRG1导致nEGFR的积聚，从而挽救了因缺乏Axl而导致的缺陷。总而言之，这些数据揭示了Ax1在调节EGFR核转位中以前未被认识到的作用，并表明Ax1介导的SFK和NRG1的表达促进了这一过程。
The epidermal growth factor receptor (EGFR) is a therapeutic target in patients with various cancers. Unfortunately, resistance to EGFR-targeted therapeutics is common. Previous studies identified two mechanisms of resistance to the EGFR monoclonal antibody cetuximab: Nuclear translocation of EGFR bypasses the inhibitory effects of cetuximab, and the receptor tyrosine kinase AXL mediates cetuximab resistance by maintaining EGFR activation and downstream signaling. Thus, we hypothesized that AXL mediated the nuclear translocation of EGFR in the setting of cetuximab resistance. Cetuximab-resistant clones of non-small cell lung cancer in culture and patient-derived xenografts in mice had increased abundance of AXL and nuclear EGFR (nEGFR). Cellular fractionation analysis, super-resolution microscopy, and electron microcopy revealed that genetic loss of AXL reduced the accumulation of nEGFR. SRC family kinases (SFKs) and HER family ligands promote the nuclear translocation of EGFR. We found that AXL knockdown reduced the expression of the genes encoding SFK family members YES and LYN and the ligand neuregulin-1 (NRG1). AXL knockdown also decreased the interaction between EGFR and the related receptor HER3 and accumulation of HER3 in the nucleus. Overexpression of LYN and NRG1 in cells depleted of AXL resulted in accumulation of nEGFR, rescuing the deficit induced by lack of AXL. Collectively, these data uncover a previously unrecognized role for AXL in regulating the nuclear translocation of EGFR and suggest that AXL-mediated SFK and NRG1 expression promote this process.
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影响因子：
11.8
作者：
Chou, Ruey-Hwang;Wang, Ying-Nai;Hsieh, Yi-Hsien;Li, Long-Yuan;Xia, Weiya;Chang, Wei-Chao;Chang, Ling-Chu;Cheng, Chien-Chia;Lai, Chien-Chen;Hsu, Jennifer L.;Chang, Wei-Jung;Chiang, Shu-Ya;Lee, Hong-Jen;Liao, Hsin-Wei;Chuang, Pei-Huan;Chen, Hui-Yu;Wang, Hung-Ling;Kuo, Sheng-Chu;Chen, Chung-Hsuan;Yu, Yung-Luen;Hung, Mien-Chie
通讯作者：
Hung, Mien-Chie
影响因子：
20.3
作者：
Ghosh, Asish K.;Secreto, Charla;Kay, Neil E.
通讯作者：
Kay, Neil E.
影响因子：
4.8
作者：
Demory, Michelle L.;Boerner, Julie L.;Parsons, Sarah J.
通讯作者：
Parsons, Sarah J.
影响因子：
50.3
作者：
Elkabets M;Pazarentzos E;Juric D;Sheng Q;Pelossof RA;Brook S;Benzaken AO;Rodon J;Morse N;Yan JJ;Liu M;Das R;Chen Y;Tam A;Wang H;Liang J;Gurski JM;Kerr DA;Rosell R;Teixidó C;Huang A;Ghossein RA;Rosen N;Bivona TG;Scaltriti M;Baselga J
通讯作者：
Baselga J
影响因子：
4.8
作者：
Biscardi, JS;Maa, MC;Parsons, SJ
通讯作者：
Parsons, SJ