Multi-layered proteomic analyses decode compositional and functional effects of cancer mutations on kinase complexes.

Nature Communications
Martin MehnertRuedi Aebersold

Abstract

Rapidly increasing availability of genomic data and ensuing identification of disease associated mutations allows for an unbiased insight into genetic drivers of disease development. However, determination of molecular mechanisms by which individual genomic changes affect biochemical processes remains a major challenge. Here, we develop a multilayered proteomic workflow to explore how genetic lesions modulate the proteome and are translated into molecular phenotypes. Using this workflow we determine how expression of a panel of disease-associated mutations in the Dyrk2 protein kinase alter the composition, topology and activity of this kinase complex as well as the phosphoproteomic state of the cell. The data show that altered protein-protein interactions caused by the mutations are associated with topological changes and affected phosphorylation of known cancer driver proteins, thus linking Dyrk2 mutations with cancer-related biochemical processes. Overall, we discover multiple mutation-specific functionally relevant changes, thus highlighting the extensive plasticity of molecular responses to genetic lesions.

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Citations

Jan 13, 2021·Molecular Systems Biology·Alicia L RichardsNevan J Krogan
Dec 31, 2020·The Journal of Biological Chemistry·Vasudha TandonSourav Banerjee
Feb 12, 2021·Expert Review of Proteomics·Vivian Weiwen XueWilliam Chi Cho
Feb 18, 2021·Protein Science : a Publication of the Protein Society·Xiaoting TangJames E Bruce
Jul 3, 2021·International Journal of Molecular Sciences·Mattias F Lindberg, Laurent Meijer
Aug 17, 2021·Current Opinion in Chemical Biology·Helisa H WippelJames E Bruce

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Methods Mentioned

BETA
nuclear translocation
pulldown
size-exclusion chromatography
xenograft
affinity purification
PCR
transfection
gene knock-out
FACS
electrophoresis

Software Mentioned

Xcalibur
OpenSWATH
SCIEX Analyst
Image J Fiji
MyriMatch
Functional
TRIC
xProphet
- viz
TANDEM

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