Meta-cancer phosphoproteomic analysis unveils association of Tau phosphosites with DNA damage response

Introduction: The microtubule-associated protein Tau, a key regulator of microtubule stability, is associated with neuronal function and neurodegeneration. Emerging evidence indicates that Tau also participates in cancer-related signalling. However, a systematic understanding of Tau phosphorylation across cancers remains limited. Methods: We performed an integrative analysis of human cellular phosphoproteomics datasets to examine the Tau phosphorylation beyond its canonical neuronal roles. Results: The comprehensive analysis of global cellular phosphoproteomics datasets revealed that the Tau phosphosites, such as S519, S713, S717, and S721, were present across various experimental conditions. The co-regulation study revealed that a comprehensive network of phosphosites in other proteins (PsOPs) exhibited either positive or negative co-regulation with these Tau phosphosites, suggesting unique site-specific phosphorylation dynamics. Considering the specific functional characterisation of Tau phosphosites, we employed a global co-regulation analysis by assessing the phosphosite-specific functions of co-regulated PsOPs, including binary interactors, complex interactors, and upstream kinases. The functional roles that can be inferred from the co-regulation patterns show cancer-related processes, such as DNA damage response, DNA repair, cell motility, and cell growth. The co-regulation analysis showed mutual regulation among S713, S717, and S721, indicating coordinated phosphorylation within Tau, which was further substantiated by the co-occurrence analysis. Additionally, the upstream kinases identified for Tau, such as CDK12/13/14/16, GSK3B, RPS6KA3, and CSNK1E, are involved in DNA damage response and carcinogenesis. These results provide a phosphosite-centric view of Tau regulation and its signalling networks in cancer, underscoring the relevance of Tau phosphosites beyond neuronal biology.