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) , , , such as
AKAP8 , AKAP11
, WAS protein family, member 1
(WASF1(WAVE1)) , A kinase anchor protein 13
(LBC)  and others. Moreover, AKAPs may
participate in PKA regulation  and/ or in
governing PKA activity .
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 .
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
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 .
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 .
cAMP-independent activation of
PKA via NFKBIA and
NFKBIB might be a general response to vasoactive peptides
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 , .
In addition, PKA-cat may be regulated by
3-phosphoinositide dependent protein kinase-1 (PDK-1) , Protein kinase (cAMP-dependent, catalytic) inhibitors
(PKI) , Protein phosphatase 1, regulatory
(inhibitor) subunit 1B (DARPP-32) .
PKA and DARPP-32 form
feedback-regulated transmission of nerve impulse 
PKA plays very diverse roles
in the cell. It participate in regulation of cell cycle and proliferation
, metabolism , transmission of nerve impulses , cytoskeleton remodeling , , muscle contraction
, , cell survival  and other cell
One of the most important targets of PKA is a cAMP
responsive element binding protein 1 (CREB1) .
- Cooper DM
Compartmentalization of adenylate cyclase and cAMP signalling.
Biochemical Society transactions 2005 Dec;33(Pt 6):1319-22
- Dell'Acqua ML, Smith KE, Gorski JA, Horne EA, Gibson ES, Gomez LL
Regulation of neuronal PKA signaling through AKAP targeting dynamics.
European journal of cell biology 2006 Jul;85(7):627-33
- McConnachie G, Langeberg LK, Scott JD
AKAP signaling complexes: getting to the heart of the matter.
Trends in molecular medicine 2006 Jul;12(7):317-23
- Landsverk HB, Carlson CR, Steen RL, Vossebein L, Herberg FW, Tasken K, Collas P
Regulation of anchoring of the RIIalpha regulatory subunit of PKA to AKAP95 by threonine phosphorylation of RIIalpha: implications for chromosome dynamics at mitosis.
Journal of cell science 2001 Sep;114(Pt 18):3255-64
- Tanji C, Yamamoto H, Yorioka N, Kohno N, Kikuchi K, Kikuchi A
A-kinase anchoring protein AKAP220 binds to glycogen synthase kinase-3beta (GSK-3beta ) and mediates protein kinase A-dependent inhibition of GSK-3beta.
The Journal of biological chemistry 2002 Oct 4;277(40):36955-61
- Rawe VY, Payne C, Navara C, Schatten G
WAVE1 intranuclear trafficking is essential for genomic and cytoskeletal dynamics during fertilization: cell-cycle-dependent shuttling between M-phase and interphase nuclei.
Developmental biology 2004 Dec 15;276(2):253-67
- Diviani D, Baisamy L, Appert-Collin A
AKAP-Lbc: a molecular scaffold for the integration of cyclic AMP and Rho transduction pathways.
European journal of cell biology 2006 Jul;85(7):603-10
- Cooper DM
Regulation and organization of adenylyl cyclases and cAMP.
The Biochemical journal 2003 Nov 1;375(Pt 3):517-29
- Dousa TP
Cyclic-3',5'-nucleotide phosphodiesterase isozymes in cell biology and pathophysiology of the kidney.
Kidney international 1999 Jan;55(1):29-62
- Chaturvedi D, Poppleton HM, Stringfield T, Barbier A, Patel TB
Subcellular localization and biological actions of activated RSK1 are determined by its interactions with subunits of cyclic AMP-dependent protein kinase.
Molecular and cellular biology 2006 Jun;26(12):4586-600
- Zhong H, SuYang H, Erdjument-Bromage H, Tempst P, Ghosh S
The transcriptional activity of NF-kappaB is regulated by the IkappaB-associated PKAc subunit through a cyclic AMP-independent mechanism.
Cell 1997 May 2;89(3):413-24
- Dulin NO, Niu J, Browning DD, Ye RD, Voyno-Yasenetskaya T
Cyclic AMP-independent activation of protein kinase A by vasoactive peptides.
The Journal of biological chemistry 2001 Jun 15;276(24):20827-30
- Zhang L, Duan CJ, Binkley C, Li G, Uhler MD, Logsdon CD, Simeone DM
A transforming growth factor beta-induced Smad3/Smad4 complex directly activates protein kinase A.
Molecular and cellular biology 2004 Mar;24(5):2169-80
- Yang H, Lee CJ, Zhang L, Sans MD, Simeone DM
Regulation of transforming growth factor beta-induced responses by protein kinase A in pancreatic acinar cells.
American journal of physiology. Gastrointestinal and liver physiology 2008 Jul;295(1):G170-G178
- Moore MJ, Kanter JR, Jones KC, Taylor SS
Phosphorylation of the catalytic subunit of protein kinase A. Autophosphorylation versus phosphorylation by phosphoinositide-dependent kinase-1.
The Journal of biological chemistry 2002 Dec 6;277(49):47878-84
- Lum H, Hao Z, Gayle D, Kumar P, Patterson CE, Uhler MD
Vascular endothelial cells express isoforms of protein kinase A inhibitor.
American journal of physiology. Cell physiology 2002 Jan;282(1):C59-66
- Nishi A, Bibb JA, Snyder GL, Higashi H, Nairn AC, Greengard P
Amplification of dopaminergic signaling by a positive feedback loop.
Proceedings of the National Academy of Sciences of the United States of America 2000 Nov 7;97(23):12840-5
- Kotani S, Tanaka H, Yasuda H, Todokoro K
Regulation of APC activity by phosphorylation and regulatory factors.
The Journal of cell biology 1999 Aug 23;146(4):791-800
- Brushia RJ, Walsh DA
Phosphorylase kinase: the complexity of its regulation is reflected in the complexity of its structure.
Frontiers in bioscience : a journal and virtual library 1999 Sep 15;4:D618-41
- McDonald BJ, Amato A, Connolly CN, Benke D, Moss SJ, Smart TG
Adjacent phosphorylation sites on GABAA receptor beta subunits determine regulation by cAMP-dependent protein kinase.
Nature neuroscience 1998 May;1(1):23-8
- Zhou R, Cao X, Watson C, Miao Y, Guo Z, Forte JG, Yao X
Characterization of protein kinase A-mediated phosphorylation of ezrin in gastric parietal cell activation.
The Journal of biological chemistry 2003 Sep 12;278(37):35651-9
- Gerits N, Mikalsen T, Kostenko S, Shiryaev A, Johannessen M, Moens U
Modulation of F-actin rearrangement by the cyclic AMP/cAMP-dependent protein kinase (PKA) pathway is mediated by MAPK-activated protein kinase 5 and requires PKA-induced nuclear export of MK5.
The Journal of biological chemistry 2007 Dec 21;282(51):37232-43
- Takimoto E, Soergel DG, Janssen PM, Stull LB, Kass DA, Murphy AM
Frequency- and afterload-dependent cardiac modulation in vivo by troponin I with constitutively active protein kinase A phosphorylation sites.
Circulation research 2004 Mar 5;94(4):496-504
- Diviani D
Modulation of cardiac function by A-kinase anchoring proteins.
Current opinion in pharmacology 2008 Apr;8(2):166-73
- Sastry KS, Karpova Y, Prokopovich S, Smith AJ, Essau B, Gersappe A, Carson JP, Weber MJ, Register TC, Chen YQ, Penn RB, Kulik G
Epinephrine protects cancer cells from apoptosis via activation of cAMP-dependent protein kinase and BAD phosphorylation.
The Journal of biological chemistry 2007 May 11;282(19):14094-100
- Thomson DM, Herway ST, Fillmore N, Kim H, Brown JD, Barrow JR, Winder WW
AMP-activated protein kinase phosphorylates transcription factors of the CREB family.
Journal of applied physiology (Bethesda, Md. : 1985) 2008 Feb;104(2):429-38