PTPRR (protein tyrosine phosphatase receptor type R) is a neuronal phosphatase that functions as a physiological regulator of mitogen-activated protein kinase (MAPK) signaling. PTPRR sequesters active MAPKs such as MAPK1, MAPK3, and MAPK14 in the cytoplasm through binding to a dephosphorylated kinase-interacting motif (KIM); phosphorylation by protein kinase A releases MAPKs for nuclear translocation and activation 1. Multiple PTPRR isoforms (PTPBR7, PTP-SL, and cytosolic variants) localize to distinct subcellular compartments including endosomes, Golgi, and cell surface, suggesting differential roles in growth-factor-induced retrograde signaling 1. Cerebellar function represents PTPRR's primary clinical relevance. PTPRR-deficient mice display motor coordination and balance deficits, implicating PTPRR in cerebellar synaptic plasticity and potentially hereditary cerebellar ataxias 21. PTPRR dysregulation associates with multiple malignancies: in colorectal cancer, Parvimonas micra promotes progression by suppressing PTPRR via miR-218-5p upregulation, thereby activating Ras/ERK/c-Fos signaling 3. In RAS-mutant lung adenocarcinoma, epigenetic PTPRR silencing promotes tumorigenesis; HDAC inhibition restores PTPRR expression and synergizes with SHP2 inhibition to suppress ERK phosphorylation and tumor progression 4. PTPRR polymorphisms associate with major depressive disorder pathogenesis 5. Therapeutically, PTPRR upregulation via ADSCs suppresses ERK signaling in idiopathic pulmonary fibrosis 6, while selective PTPRR inhibitors show promise for neurodegenerative disease treatment 7.