In Silico Phosphoproteomic Profiling of the MAP3K3 Signaling Network

Background: Mitogen-activated protein kinase kinase kinase 3 (MAP3K3) is a serine/threonine kinase that exhibits oncogenic activity in various cancers. Despite the established role of MAP3K3 in signal transduction, its phosphosignaling landscape, including the mechanisms underlying its activation and the identification of its upstream kinases and downstream substrates, remains poorly characterized. Methods: To explore this network, we analyzed the global phosphoproteomics datasets to identify predominant sites of MAP3K3. Co-concordance and co-occurrence analyses were conducted to characterize the functional significance of site-specific phosphorylation of MAP3K3. Results: From the 588 profiling datasets and 124 differential datasets, we identified S340, S337, and S166 as predominant phosphosites. We then categorized the phosphosites in other proteins (PsOPs), which were positively and negatively co-concordant with the predominant sites of MAP3K3. From the known and predicted upstream kinases, substrates, and interactors, we isolated the PsOPs that have a role in carcinogenesis. Conclusions: Finally, by integrating these co-concordance data with the currently known and predicted upstream kinases, substrates, and interactors, we constructed a phosphosignaling network of MAP3K3-driven carcinogenesis. This network provides insights into the potential upstream kinases and substrates of MAP3K3 in the context of carcinogenesis.