Pathway maps

Signal transduction_PKA signaling
Signal transduction_PKA signaling

Object List (links open in MetaCore):

G-protein alpha-12 family, WASF1(WAVE1), LBC, G-protein alpha-i family, AKAP2, ATP cytosol, PDE3B, SMAD3, Androgen receptor, KDELR, AKAP7 gamma, PCTK1, 4.6.1.1, AKAP12, SMAD4, Anaphase-promoting complex (APC), GABA-A receptor beta-2 subunit, Ryanodine receptor 1, Troponin I, cardiac, AKAP8, 3.1.4.17, AKAP11, PHK beta, GABA-A receptor beta-3 subunit, PKA-cat alpha, CREB1, cAMP, G-protein alpha-s, GSK3 alpha/beta, AKAP3, Adenylate cyclase, PDK (PDPK1), GABA-A receptor beta-1 subunit, PKA-reg (cAMP-dependent), PDE4D, PKA-cat (cAMP-dependent), DARPP-32, PKA-reg type II (cAMP-dependent), NFKBIA, Meprin A, beta, AKAP82, AMP, PDE3A, PKI, PHK gamma, PDE4A, NFKBIB, PP2A regulatory, BAD, p90RSK1, G-protein alpha-13

Description

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 cAM P. 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:

  1. Cooper DM
    Compartmentalization of adenylate cyclase and cAMP signalling. Biochemical Society transactions 2005 Dec;33(Pt 6):1319-22
  2. 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
  3. 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
  4. 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
  5. 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
  6. 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
  7. 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
  8. Cooper DM
    Regulation and organization of adenylyl cyclases and cAMP. The Biochemical journal 2003 Nov 1;375(Pt 3):517-29
  9. Dousa TP
    Cyclic-3',5'-nucleotide phosphodiesterase isozymes in cell biology and pathophysiology of the kidney. Kidney international 1999 Jan;55(1):29-62
  10. 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
  11. 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
  12. 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
  13. 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
  14. 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
  15. 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
  16. 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
  17. 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
  18. 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
  19. 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
  20. 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
  21. 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
  22. 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
  23. 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
  24. Diviani D
    Modulation of cardiac function by A-kinase anchoring proteins. Current opinion in pharmacology 2008 Apr;8(2):166-73
  25. 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
  26. 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