An Assembly of the Global Phosphoproteomic Network of an Underexplored Kinase CDK17: Possible Implications in Cell Cycle Regulation

Abstract

Cyclin-dependent kinase 17 (CDK17) is an understudied member of the PCTAIRE family of CDKs, with phosphorylation-guided molecular mechanism being underexplored. In this study, an in-depth mass spectrometry-based phosphoproteomics data integration and harmonization, coupled with replicable statistical analysis, was performed to understand the phosphorylation landscape of CDK17. High-confidence phosphorylation sites of CDK17 were derived from 711 phosphoproteomics profiling studies, where 176 datasets showed differential phosphorylation of CDK17. Among 13 identified phosphorylation sites of CDK17, S180, S137, and S146 were prominently detected in 75% of all the datasets. Notably, sequence conservation of CDK17 (S146, S137, and S180) with CDK16 (S119, S110, and S153) and CDK18 (S98, S89, and S132), respectively, was observed, where CDK16 (S119) is a part of the binding motif for multiple upstream kinases, 14-3-3 protein, and CCNYL1. Furthermore, conserved co-regulatory patterns of other proteins were identified as compared with CDK17 phosphorylation, which revealed 19 upstream kinases, 164 downstream substrates, and several interactors of CDK17, which conserved co-regulatory patterns across diverse biological contexts. Statistical analysis revealed phosphoregulation of CDK17 through other kinases, regulation of CDK17 substrates, protein–protein interactions, and conserved co-differential regulation in multiple datasets. Specifically, this analysis derived through global data integration with a replicable analytical framework lays a groundwork for experimental validation of CDK17 phosphorylation in its functional regulation.