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].
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