Molecular Target Synopsis
Overview
Domains and Structures
Drugs and Clinical Candidates
Druggability
Chemistry
Ligand Efficiency Plot
Pathways
Family Cladogram
Interaction Network
Gene Expression
Gene Copy Number Variation
RNAi
Mutations
Germline Genetics

PRKACA (P17612) - Overview - Molecular Target Synopsis

Protein


PRKACA, cAMP-dependent protein kinase catalytic subunit alpha
Enzyme Classification 2.7.11.11
UniProt P17612

Also Known as KAPCA_HUMAN, PRKACA, PKACA

Phosphorylates a large number of substrates in the cytoplasm and the nucleus. 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. Phosphorylates CDC25B, ABL1, NFKB1, CLDN3, PSMC5/RPT6, PJA2, RYR2, RORA and VASP. RORA is activated by phosphorylation. Required for glucose-mediated adipogenic differentiation increase and osteogenic differentiation inhibition from osteoblasts. Involved in the regulation of platelets in response to thrombin and collagen; 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. Prevents the antiproliferative and anti-invasive effects of alpha-difluoromethylornithine in breast cancer cells when activated. 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+). PSMC5/RPT6 activation by phosphorylation stimulates proteasome. Negatively regulates tight junctions (TJs) in ovarian cancer cells via CLDN3 phosphorylation. NFKB1 phosphorylation promotes NF-kappa-B p50-p50 DNA binding. Involved in embryonic development by down-regulating the Hedgehog (Hh) signaling pathway that determines embryo pattern formation and morphogenesis. Prevents meiosis resumption in prophase-arrested oocytes via CDC25B inactivation by phosphorylation. May also regulate rapid eye movement (REM) sleep in the pedunculopontine tegmental (PPT). Phosphorylates APOBEC3G and AICDA. Isoform 2 phosphorylates and activates ABL1 in sperm flagellum to promote spermatozoa capacitation. Phosphorylates HSF1; this phosphorylation promotes HSF1 nuclear localization and transcriptional activity upon heat shock (PubMed:21085490). A number of inactive tetrameric holoenzymes are produced by the combination of homo- or heterodimers of the different regulatory subunits associated with two catalytic subunits. cAMP causes the dissociation of the inactive holoenzyme into a dimer of regulatory subunits bound to four cAMP and two free monomeric catalytic subunits. The cAMP-dependent protein kinase catalytic subunit binds PJA2. Both isoforms 1 and 2 forms activate cAMP-sensitive PKAI and PKAII holoenzymes by interacting with regulatory subunit (R) of PKA, PRKAR1A/PKR1 and PRKAR2A/PKR2, respectively. Interacts with NFKB1, NFKB2 and NFKBIA in platelets; these interactions are disrupted by thrombin and collagen. Binds to ABL1 in spermatozoa and with CDC25B in oocytes. Interacts with APOBEC3G and AICDA. Interacts with RAB13; downstream effector of RAB13 involved in tight junction assembly. Found in a complex at least composed of MROH2B, PRKACA isoform 2 and TCP11 (By similarity). Interacts with MROH2B (By similarity). Isoform 2 interacts with TCP11 (By similarity). Interacts with HSF1 (PubMed:21085490).

6NO7
CRYSTAL STRUCTURE OF THE FULL-LENGTH WILD-TYPE PKA RIA HOLOENZYME
RCSB/PDB
Inspect Structure
See all 3D Structures for PRKACA

Isoforms / Transcripts (Protein Coding)


Sub-cellular localization


UniProt: PRKACA is active in the following subcellular-locations: acrosome, cell membrane, cell projection, cilium, cytoplasm, cytoplasmic vesicle, flagellum, membrane, mitochondrion, nucleus, secretory vesicle.
GO terms: PRKACA is active in the following subcellular-locations: acrosomal vesicle, calcium channel complex, cAMP-dependent protein kinase complex, centrosome, ciliary base, cytoplasm, cytosol, dendritic spine, extracellular exosome, intercellular bridge, membrane, mitochondrion, neuromuscular junction, nuclear speck, nucleoplasm, nucleotide-activated protein kinase complex, nucleus, perinuclear region of cytoplasm, plasma membrane raft, sperm flagellum, sperm midpiece.



UniProt
GO terms

Gene Copy Number Variation


In COSMIC - Cell Lines Project PRKACA has gain in 1 cell-lines, loss in 0 cell-lines and no signal in 1004 cell-lines. (see details)

Gene Expression


In NCI60, the highest expressing cell lines are: SNB_19, SNB_75, HS578T

In Array Express (RNA-seq of 675 commonly used human cancer cell lines), the highest expressing cell lines are: HCC12, NCI-H1155, SJCRH30

In Array Express (RNA-seq of long poly adenylated RNA and long non poly adenylated RNA from ENCODE cell lines), the highest expressing cell lines are: HSMM, NHLF, HMEC

(see details)

RNA Interference


PRKACA was reported in the following RNAI studies:

Cell - Large Scale Profiling of Kinase Dependencies in Cancer Cell Lines, the highest RNAi cell lines are: MDAMB134VI, SCC90. (see details)

3D Structures


For PRKACA there are:
40 structures (57 chains) solved
35 are solved in complex with at least one small molecule ligand
1 are solved with an approved drug

PRKACA is solved in complex with the approved drug(s):

IPH/PHENOL (3NX8_A).

(see details)
Molecular Target 3D Synopsis

Screening and Chemistry


PRKACA has been screened with 2081 compounds (3013 bioactivities), 154 compounds have bioactivities that show binding affinity of <= 500nM (195 bioactivities). (see details)