Inferring disruption of directed graphs using LIKA reveals altered protein phosphorylation networks in schizophrenia
Motivation: Kinases 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…
Schizophrenia is a complex human disease, and its etiology often involves dysregulation of protein functions, particularly those mediated by kinases. Kinases play a crucial role in regulating protein activity, but measuring their activity directly can be challenging. To overcome this obstacle, researchers often infer kinase activity by examining the behavior of their substrates, namely proteins that are phosphorylated.
Traditional methods, however, typically make a simplifying assumption by modeling kinase-substrate interactions as one-to-one relationships, disregarding the fact that a single substrate can be phosphorylated by multiple kinases.
In this study, LIKA, a likelihood-based framework, is introduced to address this limitation. LIKA models the many-to-many structure of kinase-substrate interactions, enabling it to efficiently infer kinase activity even from limited phosphoproteomic data. The robustness and accuracy of LIKA are validated through simulation and analysis of cell lines.
Furthermore, the application of LIKA to a phosphoproteomic dataset derived from schizophrenia and control subjects uncovers novel dysregulated kinases, shedding light on novel aspects of the disease's underlying molecular mechanisms. The LIKA implementation code, along with publicly available data, is made accessible via the GitHub repository at https://github.com/lujingz/LIKA.
Written by urgent.news from bioRxiv's reporting — not their text. Machine-written — it may contain errors, so check the original before relying on it.
