GPS-PBS: A Deep Learning Framework to Predict Phosphorylation Sites that Specifically Interact with...

Protein phosphorylation is essential for regulating cellular activities by modifying substrates at specific residues, which frequently interact with proteins containing phosphoprotein-binding domains (PPBDs) to propagate the phosphorylation signaling into downstream pathways. Although massive phosphorylation sites (p-sites) have been reported, most of their interacting PPBDs are unknown. Here, we collected 4458 known PPBD-specific binding p-sites (PBSs), considerably improved our previously developed group-based prediction system (GPS) algorithm, and implemented a deep learning plus transfer learning strategy for model training. Then, we developed a new online service named GPS-PBS, which can hierarchically predict PBSs of 122 single PPBD clusters belonging to two groups and 16 families. By comparison, GPS-PBS achieved a highly competitive accuracy against other existing tools. Using GPS-PBS, we predicted 371,018 mammalian p-sites that potentially interact with at least one PPBD, and revealed that various PPBD-containing proteins (PPCPs) and protein kinases (PKs) can simultaneously regulate the same p-sites to orchestrate important pathways, such as the PI3K-Akt signaling pathway. Taken together, we anticipate GPS-PBS can be a great help for further dissecting phosphorylation signaling networks.