cAMP-dependent protein kinase catalytic subunit (PKAc) (PKAc)

The cAMP-dependent protein kinase catalytic subunit (PKAc) is the enzymatic component of the Protein Kinase A (PKA) holoenzyme, a central mediator of the second messenger cyclic AMP (cAMP) signaling pathway (StatPearls, PMID: 30252315). In its inactive state, PKAc is sequestered by regulatory subunits; upon cAMP binding to these subunits, PKAc is released to phosphorylate a wide array of substrate proteins on serine and threonine residues. This phosphorylation regulates diverse cellular processes, including glucose and lipid metabolism, gene transcription via CREB, and ion channel activity (UniProt, P17612). Dysregulation of PKAc is linked to various pathologies, most notably through gain-of-function mutations or gene fusions. For instance, the DNAJB1-PRKACA fusion is a hallmark of fibrolamellar hepatocellular carcinoma, while somatic mutations like L206R are frequently found in adrenal tumors causing Cushing's syndrome (PubMed, PMID: 24523430; PMID: 24572368). While PKAc is a critical therapeutic target, its ubiquitous expression and involvement in fundamental physiological processes present significant challenges for achieving selective inhibition without systemic toxicity. Current drug discovery efforts are focused on identifying isoform-specific inhibitors or targeting the unique protein-protein interfaces created by oncogenic fusions.

Other names

PRKACAPRKACBPRKACGPKA-CProtein kinase A catalytic subunitcAMP-dependent protein kinase catalytic subunit alphacAMP-dependent protein kinase catalytic subunit betacAMP-dependent protein kinase catalytic subunit gamma

PKAc functions as a serine/threonine kinase that phosphorylates substrates containing the consensus motif Arg-Arg-X-Ser/Thr, following its release from the PKA regulatory subunits upon cAMP binding (UniProt, P17612; StatPearls, PMID: 30252315).