PRKACA

Description

The PRKACA (protein kinase cAMP-activated catalytic subunit alpha) is a protein-coding gene located on chromosome 19.

The catalytic subunit α of protein kinase A is a key regulatory enzyme that in humans is encoded by the PRKACA gene. This enzyme is responsible for phosphorylating other proteins and substrates, changing their activity. Protein kinase A catalytic subunit (PKA Cα) is a member of the AGC kinase family (protein kinases A, G, and C), and contributes to the control of cellular processes that include glucose metabolism, cell division, and contextual memory. PKA Cα is part of a larger protein complex that is responsible for controlling when and where proteins are phosphorylated. Defective regulation of PKA holoenzyme activity has been linked to the progression of cardiovascular disease, certain endocrine disorders and cancers.

== Discovery == Edmond H. Fischer and Edwin G. Krebs at the University of Washington discovered PKA in the late 1950s while working through the mechanisms that govern glycogen phosphorylase. They realized that a key metabolic enzyme called phosphorylase kinase was activated by another kinase that was dependent on the second messenger cyclic AMP (cAMP). They named this new enzyme the cAMP-dependent protein kinase, and proceeded to purify and characterize this new enzyme. Fischer and Krebs won the Nobel Prize in Physiology or Medicine in 1992 for this discovery and their continued work on kinases, and their counterparts the protein phosphatases. Today, this cAMP-dependent protein kinase is more simply noted as PKA. Another key event in the history of PKA occurred when Susan Taylor and Janusz Sowadski at the University of California San Diego solved the three dimensional structure of the catalytic subunit of the enzyme.

PRKACA phosphorylates a large number of substrates in the cytoplasm and the nucleus (PubMed:15642694, PubMed:15905176, PubMed:16387847, PubMed:17333334, PubMed:17565987, PubMed:17693412, PubMed:18836454, PubMed:19949837, PubMed:20356841, PubMed:21085490, PubMed:21514275, PubMed:21812984, PubMed:31112131). It phosphorylates CDC25B, ABL1, NFKB1, CLDN3, PSMC5/RPT6, PJA2, RYR2, RORA, SOX9 and VASP (PubMed:15642694, PubMed:15905176, PubMed:16387847, PubMed:17333334, PubMed:17565987, PubMed:17693412, PubMed:18836454, PubMed:19949837, PubMed:20356841, PubMed:21085490, PubMed:21514275, PubMed:21812984). PRKACA regulates the abundance of compartmentalized pools of its regulatory subunits through phosphorylation of PJA2 which binds and ubiquitinates these subunits, leading to their subsequent proteolysis (PubMed:21423175). RORA is activated by phosphorylation (PubMed:21514275). PRKACA is required for glucose-mediated adipogenic differentiation increase and osteogenic differentiation inhibition from osteoblasts (PubMed:19949837). It is involved in chondrogenesis by mediating phosphorylation of SOX9 (By similarity). PRKACA is involved in the regulation of platelets in response to thrombin and collagen; it maintains circulating platelets in a resting state by phosphorylating proteins in numerous platelet inhibitory pathways when in complex with NF-kappa-B (NFKB1 and NFKB2) and I-kappa-B-alpha (NFKBIA), but thrombin and collagen disrupt these complexes and free active PRKACA stimulates platelets and leads to platelet aggregation by phosphorylating VASP (PubMed:15642694, PubMed:20356841). PRKACA prevents the antiproliferative and anti-invasive effects of alpha-difluoromethylornithine in breast cancer cells when activated (PubMed:17333334). RYR2 channel activity is potentiated by phosphorylation in presence of luminal Ca(2+), leading to reduced amplitude and increased frequency of store overload-induced Ca(2+) release (SOICR) characterized by an increased rate of Ca(2+) release and propagation velocity of spontaneous Ca(2+) waves, despite reduced wave amplitude and resting cytosolic Ca(2+) (PubMed:17693412). PSMC5/RPT6 activation by phosphorylation stimulates proteasome (PubMed:17565987). PRKACA negatively regulates tight junctions (TJs) in ovarian cancer cells via CLDN3 phosphorylation (PubMed:15905176). NFKB1 phosphorylation promotes NF-kappa-B p50-p50 DNA binding (PubMed:15642694). PRKACA is required for phosphorylation of GLI transcription factors which inhibits them and prevents transcriptional activation of Hedgehog signaling pathway target genes (By similarity). GLI transcription factor phosphorylation is inhibited by interaction of PRKACA with SMO which sequesters PRKACA at the cell membrane (By similarity). PRKACA is involved in embryonic development by down-regulating the Hedgehog (Hh) signaling pathway that determines embryo pattern formation and morphogenesis most probably through the regulation of OFD1 in ciliogenesis (PubMed:33934390). It prevents meiosis resumption in prophase-arrested oocytes via CDC25B inactivation by phosphorylation (By similarity). PRKACA may also regulate rapid eye movement (REM) sleep in the pedunculopontine tegmental (PPT) (By similarity). It phosphorylates APOBEC3G and AICDA (PubMed:16387847, PubMed:18836454). PRKACA phosphorylates HSF1; this phosphorylation promotes HSF1 nuclear localization and transcriptional activity upon heat shock (PubMed:21085490). PRKACA acts as a negative regulator of mTORC1 by mediating phosphorylation of RPTOR (PubMed:31112131). {ECO:0000250|UniProtKB:P05132, ECO:0000250|UniProtKB:P27791, ECO:0000269|PubMed:15642694, ECO:0000269|PubMed:15905176, ECO:0000269|PubMed:16387847, ECO:0000269|PubMed:17333334, ECO:0000269|PubMed:17565987, ECO:0000269|PubMed:17693412, ECO:0000269|PubMed:18836454, ECO:0000269|PubMed:19949837, ECO:0000269|PubMed:20356841, ECO:0000269|PubMed:21085490, ECO:0000269|PubMed:21423175, ECO:0000269|PubMed:21514275, ECO:0000269|PubMed:21812984, ECO:0000269|PubMed:31112131, ECO:0000269|PubMed:33934390}

PRKACA is also known as CAFD1, PKACA, PPNAD4.

Associated Diseases

WES Whole Exome Sequencing

Clinical Exome Sequencing