Spatially interacting phosphorylation sites and mutations in cancer

• Published in: Nature communications 2021-04, Vol.12 (1), p.2313-2313, Article 2313
• Main Authors: Huang, Kuan-lin, Scott, Adam D., Zhou, Daniel Cui, Wang, Liang-Bo, Weerasinghe, Amila, Elmas, Abdulkadir, Liu, Ruiyang, Wu, Yige, Wendl, Michael C., Wyczalkowski, Matthew A., Baral, Jessika, Sengupta, Sohini, Lai, Chin-Wen, Ruggles, Kelly, Payne, Samuel H., Raphael, Benjamin, Fenyö, David, Chen, Ken, Mills, Gordon, Ding, Li
• Format: Article
• Language: English
• Subjects: 45; 45/23; 631/114; 631/61/475; 692/4028/67; 82/58; beta Catenin - metabolism; Binding Sites - genetics; Bioinformatics; Cancer; Cluster Analysis; Clustering; Computational Biology - methods; Epidermal growth factor receptors; ErbB Receptors - metabolism; Histones; Humanities and Social Sciences; Humans; Kinases; Mass Spectrometry - methods; multidisciplinary; Mutation; Neoplasms - genetics; Neoplasms - metabolism; Phosphorylation; Protein Tyrosine Phosphatase, Non-Receptor Type 12 - metabolism; Proteins; Proteomics; Proteomics - methods; Science; Science (multidisciplinary); Spectrometry
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-22481-w

Advances in mass-spectrometry have generated increasingly large-scale proteomics datasets containing tens of thousands of phosphorylation sites (phosphosites) that require prioritization. We develop a bioinformatics tool called HotPho and systematically discover 3D co-clustering of phosphosites and cancer mutations on protein structures. HotPho identifies 474 such hybrid clusters containing 1255 co-clustering phosphosites, including RET p.S904/Y928, the conserved HRAS/KRAS p.Y96, and IDH1 p.Y139/IDH2 p.Y179 that are adjacent to recurrent mutations on protein structures not found by linear proximity approaches. Hybrid clusters, enriched in histone and kinase domains, frequently include expression-associated mutations experimentally shown as activating and conferring genetic dependency. Approximately 300 co-clustering phosphosites are verified in patient samples of 5 cancer types or previously implicated in cancer, including CTNNB1 p.S29/Y30, EGFR p.S720, MAPK1 p.S142, and PTPN12 p.S275. In summary, systematic 3D clustering analysis highlights nearly 3,000 likely functional mutations and over 1000 cancer phosphosites for downstream investigation and evaluation of potential clinical relevance. Dysregulated phosphorylation is well-known in cancers, but it has largely been studied in isolation from mutations. Here the authors introduce HotPho, a tool that can discover spatial interactions between phosphosites and mutations, which are associated with activating mutation and genetic dependencies in cancer.