PKACα

PKACα (PRKACA) encodes the major catalytic α subunit of cyclic AMP-dependent protein kinase A (PKA), a serine/threonine kinase that transduces intracellular cAMP signals through phosphorylation of diverse cytoplasmic and nuclear substrates^[1][2]. In the inactive state, PKACα functions within a tetrameric PKA holoenzyme containing regulatory and catalytic subunits, and cAMP binding releases catalytic activity to control cellular differentiation, proliferation, metabolism, apoptosis, and transcriptional responses^[2][3]. Mechanistically, PKACα is a central effector of the cAMP-PKA signaling pathway and contributes to spatially organized signal transduction through interactions with regulatory subunits and A-kinase anchoring protein complexes^[1][2]. In disease settings, dysregulated PRKACA activity is strongly associated with endocrine tumorigenesis, particularly adrenal cortical hyperplasia, adrenocortical adenoma, and corticotropin-independent Cushing syndrome driven by activating mutations or genomic alterations that enhance PKA signaling^[4][5]. PRKACA is also a recurrent oncogenic component of the DNAJB1-PRKACA fusion that functions as a molecular driver of fibrolamellar hepatocellular carcinoma and serves as a widely used experimental model for studying aberrant kinase signaling in cancer^[6][7]. Compared with related catalytic isoforms, PKACα is the ubiquitously expressed and best-characterized PKA catalytic subunit, whereas PKACβ and PKACγ display more restricted tissue distribution and distinct isoform-specific expression patterns despite strong conservation of kinase function^[1][8]. For experimental applications, selective pharmacological inhibition of PRKACA and fusion-driven kinase activity has emerged as a useful strategy for mechanistic studies and preclinical evaluation of targeted therapies in PRKACA-dependent tumor models^[7].