The Phosphoproteomic Landscape of CD2AP: A Comprehensive Review of Kinase Networks and Disease Implications.

CD2-associated protein (CD2AP) is a multifunctional adaptor linking membrane receptors to the actin cytoskeleton, ensuring slit diaphragm integrity, regulating synaptic proteostasis, and facilitating cytoskeletal remodeling. Dysregulation of CD2AP contributes to proteinuric kidney disease, Alzheimer's disease, and tumor progression. This review provides a comprehensive overview of the structural and functional characteristics of CD2AP, its phosphorylation landscape, and potential regulatory roles. By integrating 3,825 publicly available phosphoproteomic research articles with data obtained from kinase prediction tools, the study offers information on predominant phosphosites, upstream kinases, binary interactors, and disease associations of CD2AP. We identified 45 class I phosphosites with S224, S233, S256, S458, S510, and S514 being frequently regulated across biological contexts. Predictive kinase-substrate mapping and co-regulation analysis highlighted several upstream kinases whose phosphorylation patterns positively co-regulate with CD2AP modification. Co-regulated proteins associated with Alzheimer's and kidney disease, and several phosphoproteins were associated with cell movement and cancer progression. Overall, these findings position CD2AP as a dynamic signaling hub coordinating disease-related pathways.