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

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.

We performed an integrative analysis of human cellular phosphoproteomics datasets to examine the Tau phosphorylation beyond its canonical neuronal roles.

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.