A recent study by Dr. XIE Dong’s group from Shanghai Institute of Nutrition and Health (SINH) of the Chinese Academy of Sciences (CAS) revealed the important role of PPDPF in the development of PDAC and provided a potential therapeutic strategy for PDAC. This work entitled “PPDPF promotes the development of mutant KRAS-driven pancreatic ductal adenocarcinoma by regulating the GEF activity of SOS1” was published online in Advanced Science on Dec. 1st, 2022.
Pancreatic ductal adenocarcinoma (PDAC) is the sixth most common cause of death from cancer worldwide. The overall 5-year survival rate for pancreatic cancer is less than 5%. KRAS mutations occur in up to 98% of PDAC. RAS guanine nucleotide exchange factor (GEF), such as SOS1 is recruited to plasma membrane and catalyzes the exchange of GDP for GTP on RAS to turn on the signaling upon EGFR activation. Previous study has reported that GEF could bind GTP. However, little is known about the significance of GTP-binding for GEF and whether SOS1 could bind GTP.
Pancreatic progenitor cell differentiation and proliferation factor (PPDPF) was first reported in zebrafish. PPDPF is an exocrine cell regulator, which has potential PDZ, SH2, SH3 domain binding sites and a GTP binding site. The biological function of PPDPF in pancreatic cancer remains unknown.
Here, the current study revealed that the expression of PPDPF was increased in pancreatic cancer, and patients with high PPDPF expression have a worse prognosis. Knockout of PPDPF significantly inhibited tumor development in the mouse models of mutant KRAS-driven PDAC.
Meanwhile, this study provides an unreported regulation of SOS1. Researchers found that PPDPF interacted with SOS1, both of them could bind GTP, and PPDPF transferred GTP to SOS1. In addition, they identified the Ser6,7 as the GTP-binding sites in PPDPF by mass spectrum, and an integrated method was employed to analyze the most possible amino acids within SOS1 involved in the interaction with PPDPF, which were also supposed to be the GTP-receiving sites. The importance of PPDPF-SOS1 interaction, and GTP transfer from PPDPF to SOS1 in KRAS activation was proved by these evidence. On the one hand, the GTP-binding defective mutants of PPDPF (S6L/7L) could not elevate KRAS-GTP level, and almost lost the growth-promoting ability in vitro and in vivo. On the other hand, interaction between PPDPF and SOS1 mutants SOS1R1/SOS1R2 was significantly decreased. Furthermore, the GTP-binding activity, KRAS-GEF activity and tumor-promoting function of SOS1 were severely impaired when either of the two regions was destroyed. Importantly, the two regions are in proximity to KRAS-SOS1 binding site, but the mutations did not influence KRAS-SOS1 interaction.
This research has revealed the novel function of PPDPF in PPDAC, and provided a comprehensive update of the current understanding of SOS1, presenting a promising therapeutic target for this challenging malignancy.
Dr. NI Qianzhi and Ph.D student ZHU Bing are the first authors, Dr. XIE Dong and Dr. LI Jing-Jing are the corresponding authors of this publication. The study was funded by the grants from National Natural Science Foundation of China and Youth Innovation Promotion Association of CAS.
Schematic representation demonstrating the function of PPDPF in KRAS activation. (Image provided by Dr. XIE Dong's group)
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Shanghai Institute of Nutrition and Health,
Chinese Academy of Sciences
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