PTPRS (protein tyrosine phosphatase receptor type S) is a transmembrane cell surface receptor that functions as both an extracellular glycosaminoglycan-binding protein and an intracellular tyrosine phosphatase. PTPRS binds chondroitin sulfate and heparan sulfate proteoglycans with opposing effects on neuronal outgrowth; it inhibits neurite extension via chondroitin sulfate interactions while promoting growth through heparan sulfate engagement 1. As a phosphatase, PTPRS dephosphorylates neurotrophic receptor kinases and suppresses downstream Akt and MAP kinase signaling 2. It also functions as an inhibitory immune receptor on plasmacytoid dendritic cells, downregulating TLR9-mediated interferon and TNF production 3. PTPRS is required for normal pituitary and olfactory bulb development. Clinically, PTPRS dysfunction associates with multiple diseases. A neuroprotective PTPRS variant correlates with delayed Alzheimer's disease onset, particularly in males, through preservation of synaptic markers 4. Loss of PTPRS expression promotes epithelial-mesenchymal transition in neurofibromas via EGFR activation 5 and enhances glioblastoma metastatic potential and temozolomide resistance through MAPK-MEK-ERK signaling 6. Conversely, PTPRS deletion prevents intestinal inflammation by enhancing interferon responses in dendritic cells 3. These findings identify PTPRS as a context-dependent tumor suppressor with therapeutic potential through receptor activation 7.