Reconfiguring phosphorylation signaling by genetic polymorphisms affects cancer susceptibility.
Large-scale sequencing has characterized an enormous number of genetic variations (GVs), and the functional analysis of GVs is fundamental to understanding differences in disease susceptibility and therapeutic response among and within populations. Using a combination of a sequence-based predictor with known phosphorylation and protein-protein interaction information, we computationally detected 9606 potential phosSNPs (phosphorylation-related single nucleotide polymorphisms), including 720 known, disease-associated SNPs that dramatically modify the human phosSNP-associated kinase-substrate network. Further analyses demonstrated that the proteins in the network are heavily associated in various signaling and cancer pathways, while cancer genes and drug targets are significantly enriched. We re-constructed four population-specific kinase-substrate networks and found that several inherited disease or cancer genes, such as IRS1, RAF1, and EGFR, were differentially regulated by phosSNPs. Thus, phosSNPs may influence disease susceptibility and be involved in cancer development by reconfiguring phosphorylation networks in different populations. Moreover, by systematically characterizing potential phosphorylation-related cancer mutations (phosCMs) in 12 types of cancers, we observed that both types of GVs preferentially occur in the known cancer genes, while a considerable number of phosphorylated proteins, especially those over-representing cancer genes, contain both phosSNPs and phosCMs. Furthermore, it was observed that phosSNPs were significantly enriched in amplification genes identified from breast cancers and tyrosine kinase circuits of lung cancers. Taken together, these results should prove helpful for further elucidation of the functional impacts of disease-associated SNPs.
Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China.
Yongbo
Y
Wang
Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China.
Han
H
Cheng
Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China.
Zhicheng
Z
Pan
State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China.
Jian
J
Ren
Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China lzx@hust.edu.cn xueyu@hust.edu.cn.
Zexian
Z
Liu
Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China lzx@hust.edu.cn xueyu@hust.edu.cn.
Yu
Y
Xue
D019295:Computational Biology; D018450:Disease Progression; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D053858:Metabolic Networks and Pathways; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D020641:Polymorphism, Single Nucleotide; D011494:Protein Kinases / Q000235:genetics; D011499:Protein Processing, Post-Translational; D015398:Signal Transduction
D011494:Protein Kinases
genetic variation; nsSNP; phosSNP; phosSNP-associated kinase–substrate network; phosphorylation