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Multiplexed kinase interactome profiling quantifies cellular network activity and plasticity
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DOI：10.1016/j.molcel.2023.01.015.png)
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Abstract
En 中文
Dynamic changes in protein-protein interaction (PPI) networks underlie all physiological cellular functions and drive devastating human diseases. Profiling PPI networks can, therefore, provide critical insight into dis-ease mechanisms and identify new drug targets. Kinases are regulatory nodes in many PPI networks; yet, facile methods to systematically study kinase interactome dynamics are lacking. We describe kinobead competition and correlation analysis (kiCCA), a quantitative mass spectrometry-based chemoproteomic method for rapid and highly multiplexed profiling of endogenous kinase interactomes. Using kiCCA, we identified 1,154 PPIs of 238 kinases across 18 diverse cancer lines, quantifying context-dependent kinase interactome changes linked to cancer type, plasticity, and signaling states, thereby assembling an extensive knowledgebase for cell signaling research. We discovered drug target candidates, including an endocytic adapter-associated kinase (AAK1) complex that promotes cancer cell epithelial-mesenchymal plasticity and drug resistance. Our data demonstrate the importance of kinase interactome dynamics for cellular signaling in health and disease.
Keywords:
ADAPTER-ASSOCIATED KINASE
DRUG-RESISTANCE
AAK1 KINASE
PROTEIN
KINOME
INHIBITORS
IDENTIFICATION
ENRICHMENT
EXPRESSION
ENDOCYTOSIS
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