KEA3: improved kinase enrichment analysis via data integration

Abstract

Phosphoproteomics and proteomics experiments capture a global snapshot of the cellular signaling network, but these methods do not directly measure kinase state. Kinase Enrichment Analysis 3 (KEA3) is a webserver application that infers overrepresentation of upstream kinases whose putative substrates are in a user-inputted list of proteins. KEA3 can be applied to analyze data from phosphoproteomics and proteomics studies to predict the upstream kinases responsible for observed differential phosphorylations. The KEA3 background database contains measured and predicted kinase-substrate interactions (KSI), kinase-protein interactions (KPI), and interactions supported by co-expression and co-occurrence data. To benchmark the performance of KEA3, we examined whether KEA3 can predict the perturbed kinase from single-kinase perturbation followed by gene expression experiments, and phosphoproteomics data collected from kinase-targeting small molecules. We show that integrating KSIs and KPIs across data sources to produce a composite ranking improves the recovery of the expected kinase. The KEA3 webserver is available at https://maayanlab.cloud/kea3.

Getting Started with the IDG KMC Datasets and Tools

“…Kinase Enrichment Analysis 3 (KEA3) (Kuleshov et al, 2021) is a web-based server application that infers overrepresented upstream kinases whose putative substrates are present in a user-inputted list of differentially-phosphorylated proteins. To infer upstream kinases, KEA3 uses a collection of kinase-substrate libraries created from processing data from several online databases.…”

De Novo multi-omics pathway analysis (DMPA) designed for prior data independent inference of cell signaling pathways

“…Similarly to UPAs ability to discover previously reported kinase substrate phosphosite relationships in available phosphoproteome data (Figure 2C,E), a kinase enrichment analysis based on reported kinase substrate phosphosite annotations was devised. To augment the significant lack of available kinase substrate phosphosite annotations, an additional method to predict the upstream kinase for phosphoproteome complexes based on reported kinase substrate proteinprotein interactions following the concepts of the current kinase enrichment benchmark method KEA3 (Kuleshov et al, 2021) was developed (see Materials and methods). The predicted upstream kinases were referenced to kinases known to be regulated by TYRO3.…”

Peritoneal metastasis of colorectal cancer (pmCRC): identification of predictive molecular signatures by a novel preclinical platform of matching pmCRC PDX/PD3D models

“…S7 B). Metascape and Kinase Enrichment Analysis [ 18 , 19 ] were used to analyze integrated proteomic and phosphoproteomic data of grouped resistant and responsive models. Differential 5-FU response of PDX models was mainly characterized by altered α6/β4 signaling (Fig.…”