cAMP-dependent protein kinase catalytic subunit alpha (PRKACA) (PRKACA)

The cAMP-dependent protein kinase catalytic subunit alpha (PRKACA) is a central enzyme in the cAMP signaling pathway, mediating the cellular response to various hormones and neurotransmitters (UniProt P17612). In its inactive state, the enzyme is sequestered within a heterotetrameric complex consisting of two regulatory and two catalytic subunits; the binding of cAMP to the regulatory subunits triggers the release of active catalytic subunits (PubMed: 24633105). Once liberated, PRKACA phosphorylates a wide range of substrate proteins at serine or threonine residues, thereby regulating critical processes such as glucose and lipid metabolism, gene transcription via CREB, and ion channel conductance (NIH: Gene ID 5566). Genetic alterations in PRKACA, such as the DNAJB1-PRKACA fusion or the L206R point mutation, are definitive drivers of fibrolamellar hepatocellular carcinoma and cortisol-producing adrenocortical adenomas, respectively (PubMed: 24577301). Although it is a validated therapeutic target, the ubiquitous expression of PKA catalytic subunits across nearly all tissues presents a significant challenge for drug development, as systemic inhibition can lead to widespread metabolic and cardiovascular side effects (PubMed: 25837246). Consequently, current therapeutic strategies are exploring isoform-specific inhibitors or the disruption of localized PKA-anchoring protein (AKAP) complexes to improve selectivity and safety (PubMed: 30104716).

Other names

PKA catalytic subunitPRKACAPKACAcAMP-dependent protein kinase catalytic subunitPKA C-alpha

Phosphorylation of serine and threonine residues on target proteins using ATP as a phosphate donor (UniProt P17612).