<br>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,Advanced Science

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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
Advanced Science ( IF 14.3 ) Pub Date : 2022-12-01 , DOI: 10.1002/advs.202202448
Qian-Zhi Ni _{1,

2} , Bing Zhu ₁ , Yan Ji ₁ , Qian-Wen Zheng ₃ , Xin Liang ₁ , Ning Ma ₄ , Hao Jiang ₅ , Feng-Kun Zhang ₁ , Yu-Rong Shang ₁ , Yi-Kang Wang ₁ , Sheng Xu ₁ , Er-Bin Zhang ₁ , Yan-Mei Yuan ₁ , Tian-Wei Chen ₁ , Fen-Fen Yin ₁ , Hui-Jun Cao ₁ , Jing-Yi Huang ₁ , Ji Xia ₁ , Xu-Fen Ding ₁ , Xiao-Song Qiu ₃ , Kai Ding ₁ , Chao Song ₆ , Wen-Tao Zhou ₆ , Meng Wu ₇ , Kang Wang ₂ , Rui Lui ₈ , Qiu Lin ₁ , Wei Chen ₉ , Zhi-Gang Li ₄ , Shu-Qun Cheng ₂ , Xiao-Fan Wang ₁₀ , Dong Xie _{1,

3,

11} , Jing-Jing Li ₁

Affiliation

CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, P. R. China.
Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, 200433, P. R. China.
School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, P. R. China.
Department of Thoracic Surgery, Section of Esophageal Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, 200030, P. R. China.
Department of Biomedical Informatics, School of Life Sciences, Central South University, Changsha, 410013, P. R. China.
Department of Pancreatic Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, P. R. China.
Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, 200031, P. R. China.
State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, 200438, P. R. China.
Cancer Institute of Integrated Traditional Chinese and Western Medicine, Tongde Hospital of Zhejiang Province, Hangzhou, Zhejiang, 310012, P. R. China.
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, 27710, USA.
NHC Key Laboratory of Food Safety Risk Assessment, China National Center for Food Safety Risk Assessment, Beijing, 100022, P. R. China.

鸟嘌呤核苷酸交换因子 (GEF) SOS1 催化 RAS 上 GDP 交换为 GTP。然而，对 GEF 活动的监管仍然难以捉摸。在这里，作者报告说 PPDPF 是 SOS1 的重要调节因子。 PPDPF在胰腺导管腺癌（PDAC）中的表达显着增加，与PDAC患者的不良预后和复发相关。 PPDPF 的过表达可促进 PDAC 细胞在体外和体内的生长，而 PPDPF 敲除则发挥相反的作用。在 KRAS ^G12D驱动的 PDAC 遗传小鼠模型中，胰腺特异性 PPDPF 缺失可显着抑制肿瘤的发展。 PPDPF可以结合GTP并将GTP转移到SOS1。 GTP 结合位点的突变严重损害了 PPDPF 的促肿瘤作用。一致的是，介导 SOS1-PPPDF 相互作用的关键氨基酸的突变会显着损害 SOS1 的 GEF 活性。因此，本研究展示了一种通过 PPDPF-SOS1 轴激活 KRAS 的新模型，并为 PDAC 提供了一个有前景的治疗靶点。

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更新日期：2022-12-01

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