Journal
ADVANCED SCIENCE
Volume 10, Issue 2, Pages -Publisher
WILEY
DOI: 10.1002/advs.202202448
Keywords
KRAS; pancreatic ductal adenocarcinoma; pancreatic progenitor cell differentiation; proliferation factor; SOS1
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This study reveals that PPDPF functions as an important regulator of SOS1 and promotes tumor development in pancreatic ductal adenocarcinoma (PDAC) through the PPDPF-SOS1 axis. This finding provides a potential therapeutic target for PDAC.
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 KRAS(G12D)-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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