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K63\u2010linked ubiquitination is one of the vital post\u2010translational modifications of proteins that are involved in the activation of protein kinases and protein trafficking during cell survival and proliferation. It also contributes to the development of various disorders including cancer, neurodegeneration and cardiac hypertrophy. In this review, we summarize the role of K63\u2010linked ubiquitination signalling in protein kinase activation and its implications in cardiac hypertrophy. 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