PRKAR2B encodes the type II-beta regulatory subunit of protein kinase A (PKA), a key component of the cAMP-dependent signaling pathway. As a regulatory subunit, PRKAR2B binds to PKA catalytic subunits and mediates membrane localization through interaction with anchoring proteins, thereby modulating cAMP-dependent signal transduction at multiple cellular compartments including the post-synapse, centrosome, and plasma membrane. PRKAR2B plays a documented role in sleep-wake cycle regulation; 1 identified PRKAR2B as a sleep control gene, with PKA signaling via this regulatory subunit functioning as a wake-promoting kinase at excitatory post-synapses, opposing the sleep-promoting effects of calcineurin and protein phosphatase 1. The gene has emerged as significant in cancer biology: in castration-resistant prostate cancer, PRKAR2B is upregulated and promotes metastasis by activating Wnt/β-catenin signaling and inducing epithelial-mesenchymal transition 2. In colorectal cancer, PRKAR2B was identified as one of four hub genes in a machine learning model for detecting liver metastasis 3. Additionally, dysregulated PRKAR2B expression is regulated by miR-200b-3p/200c-3p and the transcription factor XBP1 in prostate cancer 4, and by miR-3147 in diabetic kidney disease, where elevated miR-3147 promotes mesangial cell dysfunction via PRKAR2B 5. Clinically, PRKAR2B represents a potential therapeutic target in cancers driven by dysregulated cAMP signaling, particularly castration-resistant prostate cancer, where targeting PRKAR2B-mediated Wnt/β-catenin activation may inhibit metastatic progression.