Mixed Lineage Kinase 3 phosphorylates prolyl-isomerase PIN1 and potentiates GLI1 signaling in pancreatic cancer development.
Mixed Lineage Kinase 3 phosphorylates prolyl-isomerase PIN1 and potentiates GLI1 signaling in pancreatic cancer development.
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混合谱系激酶3使脯氨酰异构酶PIN1发生磷酸化，并在胰腺癌发展过程中增强GLI1信号传导。
DOI：
10.1016/j.canlet.2021.04.015
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发表时间：
2021-09-01
期刊：
影响因子：
9.7
通讯作者：
Rana A
中科院分区：
文献类型：
--
作者：
Viswakarma N;Sondarva G;Principe DR;Nair RS;Kumar S;Singh SK;Das S;Sinha SC;Grippo PJ;Grimaldo S;Giulianotti PC;Rana B;Rana A
转录因子胶质瘤相关癌基因同源物1（GLI 1）由音速刺猬（SHH）级联激活，是胰腺导管腺癌（PDAC）的既定驱动因子。然而，针对上游刺猬信号传导的疗法在临床试验中几乎没有显示出任何功效。在这里，我们确定混合谱系激酶3（MLK 3）作为致癌GLI 1的药物调节剂。之前，我们报道了MLK 3在S138位点磷酸化肽基脯氨酰异构酶PIN 1，PIN 1-pS138易位到细胞核。在这份报告中，我们确定GLI 1作为PIN 1-pS138的靶点之一，并证明PIN 1-pS138在人PDAC中上调，并与GLI 1和MLK 3表达的上调密切相关。此外，我们还确定了GLI 1上的两个新的磷酸化位点T394和S1089，它们直接被MLK 3磷酸化以促进GLI 1核转位、转录活性和细胞增殖。此外，CEP-1347对MLK 3的药理学抑制促进PDAC细胞系中的细胞凋亡，降低肿瘤负荷，延长生存期，并降低PDAC的Pdx 1-Cre x LSL-KRASG 12 D x LSL-TP 53 R172 H（KPC）小鼠模型中的GLI 1表达。这些研究结果共同表明，MLK 3是致癌GLI 1的重要调节因子，靶向MLK 3的疗法值得考虑用于PDAC患者的管理。
The transcription factor Glioma-Associated Oncogene Homolog 1 (GLI1) is activated by sonic hedgehog (SHH) cascade and is an established driver of pancreatic ductal adenocarcinoma (PDAC). However, therapies targeting upstream hedgehog signaling have shown little to no efficacy in clinical trials. Here, we identify Mixed Lineage Kinase 3 (MLK3) as a druggable regulator of oncogenic GLI1. Earlier, we reported that MLK3 phosphorylated a peptidyl-prolyl isomerase PIN1 on the S138 site, and the PIN1-pS138 translocated to the nucleus. In this report, we identify GLI1 as one of the targets of PIN1-pS138 and demonstrate that PIN1-pS138 is upregulated in human PDAC and strongly associates with the upregulation of GLI1 and MLK3 expression. Moreover, we also identified two new phosphorylation sites on GLI1, T394, and S1089, which are directly phosphorylated by MLK3 to promote GLI1 nuclear translocation, transcriptional activity, and cell proliferation. Additionally, pharmacological inhibition of MLK3 by CEP-1347 promoted apoptosis in PDAC cell lines, reduced tumor burden, extended survival, and reduced GLI1 expression in the Pdx1-Cre x LSL-KRASG12D x LSL-TP53R172H (KPC) mouse model of PDAC. These findings collectively suggest that MLK3 is an important regulator of oncogenic GLI1 and that therapies targeting MLK3 warrant consideration in the management of PDAC patients.
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DOI：
10.1074/jbc.m110.215319
发表时间：
2011-05-13
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Chou TF;Deshaies RJ
通讯作者：
Deshaies RJ
Sonic Hedgehog 旁分泌信号激活基质细胞促进胰腺癌神经周围侵袭
影响因子：
11.5
作者：
Li, Xuqi;Wang, Zheng;Xie, Keping
通讯作者：
Xie, Keping
影响因子：
6
作者：
Bao, L;Kimzey, A;Wang, DG
通讯作者：
Wang, DG
影响因子：
0.8
作者：
Kao, Shih-Han;Wang, Wen-Lung;Yang, Pan-Chyr
通讯作者：
Yang, Pan-Chyr
影响因子：
2.8
作者：
Li, Xian;Guo, Jing;Sun, Zhen-Qing
通讯作者：
Sun, Zhen-Qing