Spatially interacting phosphorylation sites and mutations in cancer

Kuan-lin Huang (), Adam D. Scott, Daniel Cui Zhou, Liang-Bo Wang, Amila Weerasinghe, Abdulkadir Elmas, Ruiyang Liu, Yige Wu, Michael C. Wendl, Matthew A. Wyczalkowski, Jessika Baral, Sohini Sengupta, Chin-Wen Lai, Kelly Ruggles, Samuel H. Payne, Benjamin Raphael, David Fenyö, Ken Chen, Gordon Mills and Li Ding ()
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Kuan-lin Huang: Icahn School of Medicine at Mount Sinai
Adam D. Scott: Washington University in St. Louis
Daniel Cui Zhou: Washington University in St. Louis
Liang-Bo Wang: Washington University in St. Louis
Amila Weerasinghe: Washington University in St. Louis
Abdulkadir Elmas: Icahn School of Medicine at Mount Sinai
Ruiyang Liu: Washington University in St. Louis
Yige Wu: Washington University in St. Louis
Michael C. Wendl: Washington University in St. Louis
Matthew A. Wyczalkowski: Washington University in St. Louis
Jessika Baral: Washington University in St. Louis
Sohini Sengupta: Washington University in St. Louis
Chin-Wen Lai: Washington University in St. Louis
Kelly Ruggles: New York University School of Medicine
Samuel H. Payne: Brigham Young University
Benjamin Raphael: Princeton University
David Fenyö: New York University School of Medicine
Ken Chen: The University of Texas MD Anderson Cancer Center
Gordon Mills: Oregon Health & Science University
Li Ding: Washington University in St. Louis

Nature Communications, 2021, vol. 12, issue 1, 1-13

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-22481-w

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