ARPP19 (cAMP-regulated phosphoprotein 19) is a protein phosphatase inhibitor that specifically suppresses protein phosphatase 2A (PP2A), particularly the PP2A:B55 holoenzyme complex, during mitosis 1. When phosphorylated at Ser-62 by Greatwall kinase, ARPP19 becomes a potent PP2A inhibitor 2, binding to the B55 regulatory subunit (specifically PPP2R2D/PR55-delta) through intrinsically disordered regions 1. This inhibition maintains elevated cyclin-B1-CDK1 kinase activity during M phase, essential for proper mitotic progression 3. ARPP19 is uniquely essential for mouse embryonic development and mitotic cell division, unlike its paralog ENSA, which suggests specialized roles despite shared PP2A inhibition mechanisms 3. The Greatwall-ARPP19-PP2A axis operates in diverse cell types, including platelets where cAMP/PKA signaling regulates ARPP19 phosphorylation 4. Beyond cell cycle control, ARPP19 dysregulation associates with cancer progression; elevated ARPP19 expression drives proliferation, migration, and invasion in colorectal and prostate cancers, partly through miR-26b-5p regulation 5 6. These findings establish ARPP19 as a critical mitotic regulator with therapeutic implications in cancer.