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Multiplexed profiling of kinase interactomes quantifies cellular network plasticity

ABSTRACT: Cancers rewire protein-protein interaction (PPI) networks to promote disease progression, making PPIs attractive drug targets. Kinases are key druggable nodes in PPI networks but high-throughput proteomics approaches to map their interactomes are lacking. We introduce kinobead competition and correlation analysis (Ki-CCA), a chemoproteomics approach combining affinity enrichment of kinases and their interaction partners with broad-selectivity binding competition to map hundreds of endogenous kinase PPIs simultaneously. We identified 2,305 PPIs of 300 kinases across 18 diverse cancer lines, demonstrating that kinase interaction networks show high plasticity between cancer types, signaling, and phenotypic states. We discovered an AAK1 complex promoting epithelial-mesenchymal transition and drug resistance, and that genetic knockdown of AAK1 complex components sensitizes cells to targeted therapy. Ki-CCA enables rapid and highly multiplexed mapping of kinome PPIs in native cell and tissue lysates, not requiring epitope tagged baits or antibodies. Our PPI database presents an important resource for cancer research.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Shao-En Ong

PROVIDER: MSV000088067 | MassIVE |

REPOSITORIES: MassIVE

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