Restricted accessResearch articleFirst published online 2026-2
Phosphorylation-Dependent Regulation and Interactions of the Neutral Amino Acid Transporter SLC6A15: Implications for Major Depression and Neuropsychiatric Disorders
SLC6A15, (sodium-dependent neutral amino acid transporter B(0)AT2), plays a crucial role in amino acid homeostasis and neuronal signaling, and it has been genetically and transcriptionally associated with major depressive disorder (MDD). However, the post-translational regulation of SLC6A15, particularly through phosphorylation, remains poorly understood. To address this knowledge gap, we report here curation of 3825 global phosphoproteomic datasets and layered statistical and bioinformatic analyses to uncover predominant phosphosites, co-phospho-regulated proteins, upstream kinases, and binary interactors of SLC6A15. Importantly, after stringent filtration, three sites, pS701, pS699, and pS687, were identified as the predominant sites of phosphorylation. Predicted upstream kinases included mitogen-activated protein kinase 3 (MAPK3) and cyclin-dependent kinase 12 (CDK12), suggesting regulatory control at these phosphorylation sites. Binary interactors such as tyrosine-protein kinase Lyn, epidermal growth factor receptor, and calnexin were found to have direct associations with stress-related pathways, indicating potential roles in stress-responsive signaling mechanisms. Pathway enrichment analysis of the high-confidence phosphosites in other proteins revealed significant enrichment of the ErbB signaling pathway, which is frequently dysregulated in MDD. Collectively, this study presents a comprehensive co-phospho-regulation-based catalog of SLC6A15, systematically mapping its key phosphorylation sites, regulatory kinases, and interaction partners. Identification of upstream kinases such as MAPK3 and CDK12 and enrichment of the ErbB signaling axis indicate a potential role of SLC6A15 in synaptic plasticity, neuronal signaling, and stress response mechanisms associated with depression. These findings uncover novel protein–protein relationships and phosphorylation-driven interactions, offering new insights into transporter regulation in neuropsychiatric disorders and potential therapeutic targets for MDD.
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