Map Key
Generic Enzyme
Generic kinase
Protein kinase
Lipid kinase
Generic phosphatase
Protein phosphatase
Lipid phosphatase
Generic phospholipase
Generic protease
Metalloprotease
G-alpha
RAS - superfamily
G beta/gamma
Regulators (GDI, GAP, GEF)
Generic channel
Ligand-gated channel
Voltage-gated channel
Transporter
Normal process
Pathological process
Positive effect
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Unspecified effect
Technical link
Disrupts in disease
Emerges in disease
Enhances in disease
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Organsim specific interaction

Generic binding protein
Receptor ligand
Cell membrane glycoprotein
Transcription factor
DNA
RNA
Compound
Inorganic ion
Predicted metabolite or user's structure
Reaction
Generic receptor
GPCR
Receptors with enzyme activity
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EPR
Golgi
Nucleus
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Peroxisome
Cytoplasm
Extracellular

Normal process
Pathological process
Binding
Cleavage
Covalent modifications
Phosphorylation
Dephosphorylation
Transformation
Transport
Catalysis
Transcription regulation
MicroRNA binding
Competition
Influence on expression
Unspecified interactions
Pharmacological effect
Toxic effect
Group relation
Complex subunit
Similarity reaction
A complex or a group
Organism specific object

Signal transduction PKA signaling


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Signal transduction PKA signaling

PKA signaling

Protein kinase cAMP-dependent ( PKA ) is an enzyme playing key role in a numberof cellular processes. In its inactivated state, PKA exists as a tetramericcomplex of two catalytic subunits ( PKA-cat alpha and PKA-cat beta) and tworegulatory subunits ( PKA-reg ) (alpha and beta type I or alpha and beta type II).PKA may be located in the cytoplasm or associated with cellular structures andorganelles depending on type PKA-reg. PKA is anchored to specificlocations within the cell by specific proteins called A kinase anchor proteins (AKAPs)[1], [2], [3], such as AKAP8 [4], AKAP11 [5], WAS protein family, member 1 (WASF1(WAVE1) ) [6], A kinase anchor protein 13 ( LBC ) [7] and others. Moreover, AKAPs may participate in PKA regulation [4] and/ or in governing PKA activity [5].

Adenosine 3',5'-monophosphate ( cAMP ) is the major activator of PKA.cAMP is a cyclic nucleotide that serves as an intracellular and, in some cases,extracellular second messenger mediating the action of many peptide or amine hormones.When both binding sites on the PKA-reg subunits are occupied by cAMP, thePKA-reg subunits undergo a conformational change that lowers their affinitytowards the PKA-cat subunits. This results in the dissociation of the holoenzymecomplex and release of the active enzyme. The PKA-cat subunits are then free tophosphorylate specific target proteins [8].

The level of intracellular cAMP is regulated by the balance between theactivities of two types of enzyme, Adenylate Cyclase and the cyclic nucleotidePhosphodiesterase (PDE). PKA may stimulate some PDEs ( PDE3A, PDE3B, PDE4A et al.) by phosphorylation producing a negative feedback [9].

Ribosomal protein S6 kinase 90kDa polypeptide 1 ( p90RSK1 ) may regulate theability of PKA to be bound to cAM P. Inactive p90RSK1 interacts withPKA-reg type I subunit. Conversely, active p90RSK1 interacts with thePKA-cat subunit. Binding of p90RSK1 to PKA-reg decreases theinteractions between PKA-reg and PKA-cat, while the binding of activep90RSK1 to PKA-cat increases interactions between PKA-cat andPKA-reg and decreases the ability of cAMP to stimulate PKA [10].

PKA can also be activated independently of cAMP. One of such activationpathways is Nuclear factor of kappa light polypeptide gene enhancer in B-cellsinhibitor(I-kB)-dependent cascade. Certain pool of PKA-cat exists in a complex with I-kBalpha and beta ( NFKBIA and NFKBIB ). Under basal conditions, NFKBIAand NFKBIB retain PKA-cat alpha in the inactive state, presumably bymasking its ATP binding site. Phosphorylation and degradation of NFKBIA andNFKBIB result in a release and activation of PKA-cat alpha [11].cAMP -independent activation of PKA via NFKBIA and NFKBIBmight be a general response to vasoactive peptides [12].

One more cAMP -independent pathway of PKA regulation is realized viaTransforming growth factor-beta ( TGF-beta )/ SMAD family member 3 and 4 (SMAD3 and SMAD4 ). Activated SMAD3 binds to SMAD4, and thiscomplex binds to the PKA-reg. This results in release of PKA-cat andactivation of the downstream target genes [13], [14].

In addition, PKA-cat may be regulated by 3-phosphoinositide dependent proteinkinase-1 ( PDK-1 ) [15], Protein kinase (cAMP-dependent, catalytic)inhibitors ( PKI ) [16], Protein phosphatase 1, regulatory (inhibitor)subunit 1B ( DARPP-32 ) [17]. PKA and DARPP-32 formfeedback-regulated transmission of nerve impulse [17]

PKA plays very diverse roles in the cell. It participate in regulationof cell cycle and proliferation [18], metabolism [19],transmission of nerve impulses [20], cytoskeleton remodeling [21], [22], muscle contraction [23], [24], cellsurvival [25] and other cell processes.

One of the most important targets of PKA is a cAMP responsive element bindingprotein 1 ( CREB1 ) [26].