Inferring disruption of directed graphs using LIKA reveals altered protein phosphorylation networks in schizophrenia

Abstract

MotivationKinases regulate a multitude of protein functions, and their dysregulation is pivotal for many human diseases. Direct measurement of kinase activity, however, is often challenging; therefore, inferring activity from the behavior of their substrates is a widely adopted strategy. Nonetheless, traditional methods typically oversimplify the underlying network, ignoring that any particular substrate can be phosphorylated by multiple kinases. ResultsWe present LIKA, a likelihood-based framework for inferring kinase activity from phosphoproteomic data. By modeling the many-to-many structure of kinase-substrate interactions, LIKA achieves high efficiency, even with limited data, while capturing network complexity. Simulation and cell line analyses confirm the robustness and accuracy of LIKA. Importantly, analysis of a phosphoproteomic dataset from schizophrenia and control subjects reveals novel dysregulated kinases. Availability and ImplementationThe implementation code and publicly available data are provided at: https://github.com/lujingz/LIKA.