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

Ni, Qian‐Zhi; Ji, Yan; Zheng, Qian-Wen; Liang, Xin; Ma, Ning; Jiang, Hao; Zhang, Feng-Kun; Shang, Yu-Rong; Wang, Yikang; Xu, Sheng; Zhang, Er‐Bin; Yuan, Yang; Chen, Tianwei; Yin, Fen‐Fen; Cao, Hui‐Jun; Huang, Jingyi; Ji, Xia; Ding, Xue; Qiu, Xiaosong; Ding, Kai; Song, Chao; Zhou, Wentao; Wu, Meng; Wang, Kang; Lui, Rui; Qiu, Lin; Chen, Wei; Li, Zhigang; Cheng, Shu-Qun; Wang, Xiaofan; Xie, Dong; Li, Jingjing

doi:10.1002/advs.202202448

Cited by 3 publications

(1 citation statement)

References 55 publications

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“…KRAS, one of the three RAS genes, can be selectively spliced to produce approximately 12 kDa-long KRAS4A and KRAS4B with nearly identical G structural domains and is one of the common genetic mutations in many human cancers, playing a central role in cancer biology [31][32][33]. PPDPF, which is highly expressed in pancreatic cancer, regulates the GEF activity of SOS1 to promote disease progression in Kras mutant pancreatic ductal carcinoma [34]. Originally named for its ability to induce hemorrhagic tumor necrosis, TNF, produced mainly by macrophages, T lymphocytes, and macrophages, is a key cytokine linking the body's immune system and in ammatory response and is highly related to the development of IDD [35,36].…”

Section: Discussionmentioning

confidence: 99%

The significance of MAPK signaling pathway in the diagnosis and subtype classification of intervertebral disc degeneration

Liu,

Chen

et al. 2023

Preprint

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Intervertebral disc degeneration (IDD) is a human aging disease related mainly to inflammation, cellular senescence, RNA/DNA methylation, and ECM. The mitogen-activated protein kinase (MAPK) signaling pathway is engaged in multiple biological functions by phosphorylating specific serine and threonine residues on target proteins through phosphorylation cascade effects, but the role and specific mechanisms of the MAPK signaling pathway in IDD are still unclear. We obtained 20 MAPK-related differential genes by differential analysis of GSE124272 and GSE150408 derived from the GEO database. To investigate the biological function of this differential gene in humans, we also performed GO and KEGG analyses. We applied PPI networks, LASSO analysis, the RF algorithm, and the SVM-RFE algorithm to identify core MAPK-related genes. We eventually obtained four hub MAPK-related genes, namely KRAS, JUN, and RAP1B, and constructed the ROC curves separately to evaluate the precision of the hub genes. To forecast the prevalence of IDD, a nomogram model was created on our four hub MAPK genes of choice. Based on these 4 hub genes, we classified IDD patients into two MAP clusters by applying the consensus clustering method and identified 1916 DEGs by analyzing the differences between the two clusters. Then, using the same method, we identified two gene clusters based on these DEGs. We used a PCA algorithm to determine the MAPK score for each sample, and in the end, we discovered that MAPK cluster A and gene cluster A had higher scores. We displayed the differing expression levels of four hub MAPK-related genes across the two clusters and their relationship with immune cell infiltration to highlight the distinctions between clusters A and B. In summary, four hub MAPK signaling pathway-related genes, KRAS, JUN, RAP1B, and TNF, could be applied to the diagnosis and subtype classification of IDD and benefit the prevention and treatment of IDD.

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Section: Discussionmentioning

confidence: 99%

The significance of MAPK signaling pathway in the diagnosis and subtype classification of intervertebral disc degeneration

Liu,

Chen

et al. 2023

Preprint

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

Zheng

et al. 2022

Advanced Science

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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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Deep Learning Methods for Binding Site Prediction in Protein Structures

Geraseva

2024

Biochem. Moscow Suppl. Ser. B

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

Cited by 3 publications

References 55 publications

The significance of MAPK signaling pathway in the diagnosis and subtype classification of intervertebral disc degeneration

The significance of MAPK signaling pathway in the diagnosis and subtype classification of intervertebral disc degeneration

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

Deep Learning Methods for Binding Site Prediction in Protein Structures

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