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].
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