Signal transduction - PKA signaling

PKA signaling

Protein kinase cAMP-dependent (PKA) is an enzyme playing key role in a number of cellular processes. In its inactivated state, PKA exists as a tetrameric complex of two catalytic subunits (PKA-cat alpha and PKA-cat beta) and two regulatory 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 and organelles depending on type PKA-reg. PKA is anchored to specific locations 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, the PKA-reg subunits undergo a conformational change that lowers their affinity towards the PKA-cat subunits. This results in the dissociation of the holoenzyme complex and release of the active enzyme. The PKA-cat subunits are then free to phosphorylate specific target proteins [8].

The level of intracellular cAMP is regulated by the balance between the activities of two types of enzyme, Adenylate Cyclase and the cyclic nucleotide Phosphodiesterase (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 the ability of PKA to be bound to cAMP. Inactive p90RSK1 interacts with PKA-reg type I subunit. Conversely, active p90RSK1 interacts with the PKA-cat subunit. Binding of p90RSK1 to PKA-reg decreases the interactions between PKA-reg and PKA-cat, while the binding of active p90RSK1 to PKA-cat increases interactions between PKA-cat and PKA-reg and decreases the ability of cAMP to stimulate PKA [10].

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

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

In addition, PKA-cat may be regulated by 3-phosphoinositide dependent protein kinase-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 form feedback-regulated transmission of nerve impulse [17]

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

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

References:

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