PPDPF Promotes the Development of Mutant KRAS-Driven Pancreatic Ductal Adenocarcinoma by Regulating the GEF Activity of SOS1.
PPDPF Promotes the Development of Mutant KRAS-Driven Pancreatic Ductal Adenocarcinoma by Regulating the GEF Activity of SOS1.
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PPDPF 通过调节 SOS1 的 GEF 活性促进突变 KRAS 驱动的胰腺导管腺癌的发展
DOI：
10.1002/advs.202202448
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发表时间：
2023-01
期刊：
影响因子：
15.1
通讯作者：
Li, Jing-Jing
中科院分区：
文献类型：
--
作者：
Ni, Qian-Zhi;Zhu, Bing;Ji, Yan;Zheng, Qian-Wen;Liang, Xin;Ma, Ning;Jiang, Hao;Zhang, Feng-Kun;Shang, Yu-Rong;Wang, Yi-Kang;Xu, Sheng;Zhang, Er-Bin;Yuan, Yan-Mei;Chen, Tian-Wei;Yin, Fen-Fen;Cao, Hui-Jun;Huang, Jing-Yi;Xia, Ji;Ding, Xu-Fen;Qiu, Xiao-Song;Ding, Kai;Song, Chao;Zhou, Wen-Tao;Wu, Meng;Wang, Kang;Lui, Rui;Lin, Qiu;Chen, Wei;Li, Zhi-Gang;Cheng, Shu-Qun;Wang, Xiao-Fan;Xie, Dong;Li, Jing-Jing
关键词：
鸟嘌呤核苷酸交换因子SOS1在RAS上催化GDP与GTP的交换。然而，对全球环境基金活动的监管仍然难以捉摸。在此，作者报道了PPDPF作为SOS1的一个重要调节因子。PPDPF在胰腺导管腺癌(PDAC)中的表达显著升高，与PDAC患者预后不良及复发有关。PPDPF过表达在体内外均能促进PDAC细胞的生长，而PPDPF基因敲除则起到相反的作用。在KrasG12D驱动的PDAC遗传小鼠模型中，胰腺特异的PPDPF缺失深刻地抑制了肿瘤的发展。PPDPF可以与GTP结合，并将GTP转移到SOS1。GTP结合位点的突变严重削弱了PPDPF的促癌作用。始终如一地，介导SOS1-PPDPF相互作用的关键氨基酸的突变显著削弱了SOS1的全球环境基金活性。因此，本研究提出了一种新的通过PPDPF-SOS1轴激活KRAS的模型，并为PDAC提供了一个有前景的治疗靶点。本研究揭示了一种通过PPDPF-SOS1轴激活KRAS的新模型。PPDPF在胰腺癌中表达上调。它可以与GTP结合并向SOS1提供GTP，从而刺激SOS1的全球环境基金活性和随后的KRAS激活。这项工作为PDAC提供了一个很有前景的治疗靶点。
The guanine nucleotide exchange factor (GEF) SOS1 catalyzes the exchange of GDP for GTP on RAS. However, regulation of the GEF activity remains elusive. Here, the authors report that PPDPF functions as an important regulator of SOS1. The expression of PPDPF is significantly increased in pancreatic ductal adenocarcinoma (PDAC), associated with poor prognosis and recurrence of PDAC patients. Overexpression of PPDPF promotes PDAC cell growth in vitro and in vivo, while PPDPF knockout exerts opposite effects. Pancreatic‐specific deletion of PPDPF profoundly inhibits tumor development in KRASG12D‐driven genetic mouse models of PDAC. PPDPF can bind GTP and transfer GTP to SOS1. Mutations of the GTP‐binding sites severely impair the tumor‐promoting effect of PPDPF. Consistently, mutations of the critical amino acids mediating SOS1–PPDPF interaction significantly impair the GEF activity of SOS1. Therefore, this study demonstrates a novel model of KRAS activation via PPDPF‐SOS1 axis, and provides a promising therapeutic target for PDAC. This study reveals a novel model of KRAS activation via PPDPF‐SOS1 axis. PPDPF is upregulated in pancreatic ductal adenocarcinoma. It can bind GTP and offer GTP to SOS1, which stimulates the GEF activity of SOS1 and subsequent activation of KRAS. This work provides a promising therapeutic target for PDAC.
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影响因子：
28.2
作者：
Collisson EA;Trejo CL;Silva JM;Gu S;Korkola JE;Heiser LM;Charles RP;Rabinovich BA;Hann B;Dankort D;Spellman PT;Phillips WA;Gray JW;McMahon M
通讯作者：
McMahon M
DOI：
10.1073/pnas.1812963116
发表时间：
2019-02-12
影响因子：
11.1
作者：
Hillig, Roman C.;Sautier, Brice;Bader, Benjamin
通讯作者：
Bader, Benjamin
DOI：
10.1126/science.1250373
发表时间：
2014-07-04
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Iversen L;Tu HL;Lin WC;Christensen SM;Abel SM;Iwig J;Wu HJ;Gureasko J;Rhodes C;Petit RS;Hansen SD;Thill P;Yu CH;Stamou D;Chakraborty AK;Kuriyan J;Groves JT
通讯作者：
Groves JT
影响因子：
4.5
作者：
Cerny AC;Altendorfer A;Schopf K;Baltner K;Maag N;Sehn E;Wolfrum U;Huber A
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Huber A
影响因子：
4
作者：
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通讯作者：
Rossman, Kent L.