PPP2R5E encodes a regulatory B-subunit of protein phosphatase 2A (PP2A), a multifunctional enzymatic complex critical for cellular signaling 1. As a regulatory subunit, PPP2R5E modulates substrate selectivity and catalytic activity of PP2A while directing enzymatic localization to specific subcellular compartments 2. PPP2R5E stabilizes microtubule crosslinking factor 1 (MTCL1) through PP2A-dependent dephosphorylation, thereby regulating microtubule organization essential for cell structure and function 2. Dysfunction of PPP2R5E is implicated in multiple disease contexts. A de novo heterozygous variant (Glu191Lys) in PPP2R5E caused decreased interaction with PP2A catalytic subunits, disrupting holoenzyme formation and manifesting as specific learning disorders, motor coordination deficits, hypotonia, and behavioral issues 1. In Alzheimer's disease, apolipoprotein E4 transcriptionally represses PPP2R5E expression and triggers demethylation of the PP2A catalytic subunit, reducing overall phosphatase activity and elevating tau phosphorylation 3. In cancer, microRNAs miR-19b and miR-23a suppress PPP2R5E expression, promoting colorectal and gastric cancer cell growth while reducing apoptosis and chemotherapy sensitivity 45. Chr14 translocations disrupting PPP2R5E are associated with developmental abnormalities, suggesting haploinsufficiency 6.