PPDPF Promotes the Development of Mutant KRAS-Driven Pancreatic Ductal Adenocarcinoma by Regulating the GEF Activity of SOS1.

Abstract

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.

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Published Version (Please cite this version)

10.1002/advs.202202448

Publication Info

Ni, Qian-Zhi, Bing Zhu, Yan Ji, Qian-Wen Zheng, Xin Liang, Ning Ma, Hao Jiang, Feng-Kun Zhang, et al. (2023). PPDPF Promotes the Development of Mutant KRAS-Driven Pancreatic Ductal Adenocarcinoma by Regulating the GEF Activity of SOS1. Advanced science (Weinheim, Baden-Wurttemberg, Germany), 10(2). p. e2202448. 10.1002/advs.202202448 Retrieved from https://hdl.handle.net/10161/26670.

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Scholars@Duke

Wang

Xiao-Fan Wang

Donald and Elizabeth Cooke Distinguished Professor of Cancer Research, in the School of Medicine

The current research in the Wang laboratory mainly focuses on the elucidation of molecular nature and signaling mechanisms associated with the initiation of cellular senescence. In addition, we continue to study changes in tumor microenvironment that promotes tumor progression and metastasis, particularly how tumor cells interact with the immune system. Ultimately, we hope that our studies in these areas to lead to the development of novel therapeutics for the treatment of various types of human cancer.


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