プロテインキナーゼＡ

シグナル伝達
四次構造
数種類の不活性な四量体ホロ酵素はホモまたはヘテロに量体を形成する調節サブユニットと2分子の触媒サブユニットの組み合わせによる。cAMPは調節サブユニット二量体に四分子のcAMPが結合し、調節サブユニット二量体と2分子の単量体触媒サブユニットに解離させる。調節サブユニットはPJA2と結合する。（PAJ2:PKAのプロテアソームによる分解に関与するE2依存性ユビキチンリガーゼ）。アイソフォーム１はPRKAR1Aと、アイソフォーム２はPRKAR2Aと相互作用する。血小板ではNFKB1、NFKB2、NFKBIAと相互作用するが、トロンビンやコラーゲンによって壊される。精子ではABL1と、卵細胞ではCDC25Bと相互作用する。
機能
GPCRにより惹起されるcAMPに依存したシグナル伝達を仲介する。PKAの活性化は、細胞の増殖、細胞周期、分化、微小管の挙動、クロマチンの凝集や脱凝集、角膜の消失に加えて細胞内輸送やイオンの動きなど、さまざまな細胞内プロセスを制御する。PJA2のリン酸化によるユビキチン化とタンパク分解により調節サブユニットの区分されたプールの量が調節される。（触媒サブユニットβ　PKAC-beta）
活性調節
ATPを含むさまざまな化合物によりアロステリックな調節を受ける。

機能

細胞質や核内の多くの基質をリン酸化する。
CDC25B（M-Phase inducer phosphatase 2; 有糸分裂の進行を導くチロシンキナーゼ）, ABL1, NFKB1, CLDN3( Claudin-3; Plays a major role in tight junction-specific obliteration of the intercellular space, through calcium-independent cell-adhesion activity), PSMC5/RPT6, PJA2, RYR2(リアノジン受容体2; Calcium channel that mediates the release of Ca2+ from the sarcoplasmic reticulum into the cytoplasm and thereby plays a key role in triggering cardiac muscle contraction./ Channel activity is modulated by phosphorylation. Phosphorylation at Ser-2808 and Ser-2814 increases the open probability of the calcium channel. Phosphorylation is increased in failing heart, leading to calcium leaks and increased cytoplasmic Ca2+ levels. Phosphorylation at Ser-2031 by PKA enhances the response to lumenal calcium ), RORA(RAR-related orphan receptor A) and VASP (Vasodilator-stimulated phosphoprotein)をリン酸化する。
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 Ca2+, leading to reduced amplitude and increased frequency of store overload-induced Ca2+ release (SOICR) characterized by an increased rate of Ca2+ release and propagation velocity of spontaneous Ca2+ waves, despite reduced wave amplitude and resting cytosolic Ca2+. 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.

α

細胞質と核内で多くの基質をリン酸化する。PJA2をリン酸化することで調節サブユニットをユビキチン化し分解に導く。
リン酸化により多くのシグナル伝達に関与するタンパク質を活性化する。

β

細胞増殖や細胞周期、分化、微小管の動き、クロマチン濃縮、角膜の分解と再構成、細胞内異動やイオンの動きなどにかかわる。PJA2のリン酸化を介して調節サブユニットを分解する。
細胞内では細胞質、細胞膜、核に分布する。単量体の触媒サブユニットが核内に移行する。

PJA2

E2依存性にE3ユビキチンリガーゼ活性を示し、cAMP依存性プロテインキナーゼのタイプ1，タイプ2α／β調節サブユニットを分解する。
PKAによる長期間の記憶過程に関与する。

CREB

cAMP応答配列に結合する転写因子。

133Serのリン酸化がDNA結合に必須である。CaMK1, CaMK2, CaMK4, PKB/AKT1 or PKB/AKT2, RPS6KA3, RPS6KA4, RPS6KA5 and SGK1によるリン酸化反応

cAMP-dependent protein kinase catalytic subunit alpha

Function
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 Ca2+, leading to reduced amplitude and increased frequency of store overload-induced Ca2+ release (SOICR) characterized by an increased rate of Ca2+ release and propagation velocity of spontaneous Ca2+ waves, despite reduced wave amplitude and resting cytosolic Ca2+. 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. Ref.11 Ref.12 Ref.13 Ref.14 Ref.15 Ref.17 Ref.19 Ref.24 Ref.25 Ref.27 Ref.28 Ref.29
Catalytic activity
ATP + a protein = ADP + a phosphoprotein.
Enzyme regulation
Allosterically activated by various compounds, including ATP. Activated by cAMP; the nucleotide acts as a dynamic and allosteric activator by coupling the two lobes of apo PKA, enhancing the enzyme dynamics synchronously and priming it for catalysis. Inhibited by H89 (N-[2-[[3-(4-Bromophenyl)-2-propenyl]amino]ethyl]-5-isoquinolinesulfonamide), spiroindoline, azole-based inhibitors, (3s)-amino-aminomethylbenzamide analogs, ARC-1032 (6-{[(2S,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxyoxolan-2-yl]formamido}-N-[(1R)-4-carbamimidamido-1-carbamoylbutyl]hexanamide), ARC-1034 (6-{[(2S,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxyoxolan-2-yl]formamido}-N-[(1R)-4-carbamimidamido-1-{[(1R)-4-carbamimidamido-1-carbamoylbutyl]carbamoyl}butyl]hexanamide), ARC-582, ARC-902 (Adc-6-aminohexanoic acid-(D-Arg)(6)-NH2), ARC-1012 ((2R)-6-amino-2-(6-{[(2S,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxyoxolan-2-yl]formamido}hexanamido)-N-(5-{[(1R)-4-carbamimidamido-1-{[(1R)-4-carbamimidamido-1-carbamoylbutyl]carbamoyl}butyl]carbamoyl}pentyl)hexanamide) and ARC-1039 (6-{[(2S,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxyoxolan-2-yl]formamido}-N-[(1R)-1-[(5-{[(1R)-4-carbamimidamido-1-{[(1R)-4-carbamimidamido-1-carbamoylbutyl]carbamoyl}butyl]carbamoyl}pentyl)carbamoyl]ethyl]he xanamide). Ref.16 Ref.20 Ref.25 Ref.31 Ref.32 Ref.33
Subunit structure
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. Ref.10 Ref.13 Ref.19 Ref.24 Ref.28
Subcellular location
Cytoplasm. Cell membrane. Nucleus By similarity. Mitochondrion By similarity. Note: Translocates into the nucleus (monomeric catalytic subunit). The inactive holoenzyme is found in the cytoplasm. Distributed throughout the cytoplasm in meiotically incompetent oocytes. Associated to mitochondrion as meiotic competence is acquired. Aggregates around the germinal vesicles (GV) at the immature GV stage oocytes By similarity. Ref.6 Ref.21 Ref.29

Isoform 2: Cell projection › cilium › flagellum. Note: Expressed in the midpiece region of the sperm flagellum. Ref.6 Ref.21 Ref.29

Tissue specificity
Isoform 1 is ubiquitous. Isoform 2 is sperm-specific and is enriched in pachytene spermatocytes but is not detected in round spermatids. Ref.6 Ref.28
Post-translational modification
Asn-3 is partially deaminated to Asp giving rise to 2 major isoelectric variants, called CB and CA respectively By similarity.

Autophosphorylated. Phosphorylation is enhanced by vitamin K2. Phosphorylated on threonine and serine residues. Phosphorylation on Thr-198 is required for full activity. Phosphorylated at Tyr-331 by activated receptor tyrosine kinases EGFR and PDGFR; this increases catalytic efficienncy

cAMP-dependent protein kinase catalytic subunit beta

Short name=PKA C-beta
EC=2.7.11.11

Function
Mediates cAMP-dependent signaling triggered by receptor binding to GPCRs. PKA activation regulates diverse cellular processes such as cell proliferation, the cell cycle, differentiation and regulation of microtubule dynamics, chromatin condensation and decondensation, nuclear envelope disassembly and reassembly, as well as regulation of intracellular transport mechanisms and ion flux. 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. Ref.10 Ref.13
Catalytic activity
ATP + a protein = ADP + a phosphoprotein.
Cofactor
Magnesium.
Enzyme regulation
Activated by cAMP.
Subunit structure
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 By similarity.
Subcellular location
Cytoplasm. Cell membrane. Nucleus By similarity. Note: Translocates into the nucleus (monomeric catalytic subunit) By similarity. The inactive holoenzyme is found in the cytoplasm By similarity. Ref.13
Tissue specificity
Isoform 1 is most abundant in the brain, with low level expression in kidney. Isoform 2 is predominantly expressed in thymus, spleen and kidney. Isoform 3 and isoform 4 are only expressed in the brain. Ref.9
Post-translational modification
Asn-3 is partially deaminated to Asp giving rise to 2 major isoelectric variants, called CB and CA respectively.

cAMP-dependent protein kinase catalytic subunit gamma

Short name=PKA C-gamma
EC=2.7.11.11

Function
Phosphorylates a large number of substrates in the cytoplasm and the nucleus.
Catalytic activity
ATP + a protein = ADP + a phosphoprotein.
Enzyme regulation
Activated by cAMP.
Subunit structure
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.
Tissue specificity
Testis specific. But important tissues such as brain and ovary have not been analyzed for the content of transcript.

cAMP-dependent protein kinase type I-alpha regulatory subunit

  • Alternative name(s):Tissue-specific extinguisher 1 / Short name=TSE1
  • Cleaved into the following chain:cAMP-dependent protein kinase type I-alpha regulatory subunit, N-terminally processed
Function
Regulatory subunit of the cAMP-dependent protein kinases involved in cAMP signaling in cells. Ref.10 Ref.20
Subunit structure
The inactive holoenzyme is composed of two regulatory chains and two catalytic chains. Activation by cAMP releases the two active catalytic monomers and the regulatory dimer. PRKAR1A also interacts with RFC2; the complex may be involved in cell survival. Interacts with AKAP4. Interacts with RARA; the interaction occurs in the presence of cAMP or FSH and regulates RARA transcriptional activity. Interacts with the phosphorylated form of PJA2. Interacts with CBFA2T3 By similarity. Interacts with PRKX; regulates this cAMP-dependent protein kinase. Interacts with C2orf88/smAKAP; this interaction may target PRKAR1A to the plasma membrane. Interacts with AICDA. Ref.8 Ref.10 Ref.11 Ref.20 Ref.24 Ref.27
Subcellular location
Cell membrane Ref.27.
Tissue specificity
Four types of regulatory chains are found: I-alpha, I-beta, II-alpha, and II-beta. Their expression varies among tissues and is in some cases constitutive and in others inducible.
Post-translational modification
The pseudophosphorylation site binds to the substrate-binding region of the catalytic chain, resulting in the inhibition of its activity.
Involvement in disease
Carney complex 1 (CNC1) [MIM:160980]: CNC is a multiple neoplasia syndrome characterized by spotty skin pigmentation, cardiac and other myxomas, endocrine tumors, and psammomatous melanotic schwannomas.

Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.26 Ref.28 Ref.31 Ref.32
Intracardiac myxoma (INTMYX) [MIM:255960]: Inheritance is autosomal recessive.
Note: The disease is caused by mutations affecting the gene represented in this entry.
Primary pigmented nodular adrenocortical disease 1 (PPNAD1) [MIM:610489]: A rare bilateral adrenal defect causing ACTH-independent Cushing syndrome. Macroscopic appearance of the adrenals is characteristic with small pigmented micronodules observed in the cortex. Clinical manifestations of Cushing syndrome include facial and truncal obesity, abdominal striae, muscular weakness, osteoporosis, arterial hypertension, diabetes. PPNAD1 is most often diagnosed in patients with Carney complex, a multiple neoplasia syndrome. However it can also be observed in patients without other manifestations.
Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.7
Acrodysostosis 1, with or without hormone resistance (ACRDYS1) [MIM:101800]: A form of skeletal dysplasia characterized by short stature, severe brachydactyly, facial dysostosis, and nasal hypoplasia. Affected individuals often have advanced bone age and obesity. Laboratory studies show resistance to multiple hormones, including parathyroid, thyrotropin, calcitonin, growth hormone-releasing hormone, and gonadotropin. However, not all patients show endocrine abnormalities.
Note: The disease is caused by mutations affecting the gene represented in this entry.

cAMP-dependent protein kinase type II-alpha regulatory subunit

Gene names
Name: PRKAR2A
Synonyms: PKR2, PRKAR2

Function
Regulatory subunit of the cAMP-dependent protein kinases involved in cAMP signaling in cells. Type II regulatory chains mediate membrane association by binding to anchoring proteins, including the MAP2 kinase.
Subunit structure
The inactive form of the enzyme is composed of two regulatory chains and two catalytic chains. Activation by cAMP produces two active catalytic monomers and a regulatory dimer that binds four cAMP molecules. Interacts with AKAP4 and CBFA2T3. Interacts with the phosphorylated form of PJA2. Interacts with MYRIP. This interaction may link PKA to components of the exocytosis machinery, thus facilitating exocytosis, including insulin release By similarity. Ref.3 Ref.7 Ref.17
Subcellular location
Cytoplasm. Cell membrane. Note: Colocalizes with PJA2 in the cytoplasm and the cell membrane. Ref.17
Tissue specificity
Four types of regulatory chains are found: I-alpha, I-beta, II-alpha, and II-beta. Their expression varies among tissues and is in some cases constitutive and in others inducible.
Post-translational modification
Phosphorylated by the activated catalytic chain.

E3 ubiquitin-protein ligase Praja-2

Short name=Praja2
EC=6.3.2.-
Alternative name(s):
RING finger protein 131

Function
Has E2-dependent E3 ubiquitin-protein ligase activity. Responsible for ubiquitination of cAMP-dependent protein kinase type I and type II-alpha/beta regulatory subunits and for targeting them for proteasomal degradation. Essential for PKA-mediated long-term memory processes. Ref.9 Ref.14
Pathway
Protein modification; protein ubiquitination.
Subunit structure
Binds ubiquitin-conjugating enzymes (E2s). In vitro, interacts with the ubiquitin-conjugating enzyme, UBE2D2. The phosphorylated form interacts with PRKAR1A, PRKAR2A and PRKAR2B. Binds the catalytic subunits of cAMP-dependent protein kinase. Ref.9 Ref.14
Subcellular location
Cytoplasm. Cell membrane. Endoplasmic reticulum membrane; Peripheral membrane protein. Golgi apparatus membrane; Peripheral membrane protein. Cell junction › synapse By similarity. Cell junction › synapse › postsynaptic cell membrane › postsynaptic density By similarity. Note: Localizes at the cytoplasmic side of endoplasmic reticulum and Golgi apparatus. Expressed in the postsynaptic density region of synapses By similarity. Colocalizes with PRKAR2A and PRKAR2B in the cytoplasm and the cell membrane. Ref.14
Sequence similarities
Contains 1 RING-type zinc finger.