title: Reciprocal regulation of PKA and Rac signaling.
abstract: Activated G protein-coupled receptors (GPCRs) and receptor tyrosine kinases relay extracellular signals through spatial and temporal controlled kinase and GTPase entities. These enzymes are coordinated by multifunctional scaffolding proteins for precise intracellular signal processing. The cAMP-dependent protein kinase A (PKA) is the prime example for compartmentalized signal transmission downstream of distinct GPCRs. A-kinase anchoring proteins tether PKA to specific intracellular sites to ensure precision and directionality of PKA phosphorylation events. Here, we show that the Rho-GTPase Rac contains A-kinase anchoring protein properties and forms a dynamic cellular protein complex with PKA. The formation of this transient core complex depends on binary interactions with PKA subunits, cAMP levels and cellular GTP-loading accounting for bidirectional consequences on PKA and Rac downstream signaling. We show that GTP-Rac stabilizes the inactive PKA holoenzyme. However, β-adrenergic receptor-mediated activation of GTP-Rac-bound PKA routes signals to the Raf-Mek-Erk cascade, which is critically implicated in cell proliferation. We describe a further mechanism of how cAMP enhances nuclear Erk1/2 signaling: It emanates from transphosphorylation of p21-activated kinases in their evolutionary conserved kinase-activation loop through GTP-Rac compartmentalized PKA activities. Sole transphosphorylation of p21-activated kinases is not sufficient to activate Erk1/2. It requires complex formation of both kinases with GTP-Rac1 to unleash cAMP-PKA-boosted activation of Raf-Mek-Erk. Consequently GTP-Rac functions as a dual kinase-tuning scaffold that favors the PKA holoenzyme and contributes to potentiate Erk1/2 signaling. Our findings offer additional mechanistic insights how β-adrenergic receptor-controlled PKA activities enhance GTP-Rac-mediated activation of nuclear Erk1/2 signaling.
authors: Institutes of Biochemistry, University of Innsbruck, A-6020 Innsbruck, Austria.
authors: Verena A
authors: VA
authors: Bachmann
authors: Anna
authors: A
authors: Riml
authors: Roland G
authors: RG
authors: Huber
authors: George S
authors: GS
authors: Baillie
authors: Klaus R
authors: KR
authors: Liedl
authors: Taras
authors: T
authors: Valovka
authors: Eduard
authors: E
authors: Stefan
mesh_terms: D045744:Cell Line, Tumor; D000242:Cyclic AMP / Q000235:genetics / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006160:Guanosine Triphosphate / Q000235:genetics / Q000378:metabolism; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D009097:Multienzyme Complexes / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000502:physiology; D011943:Receptors, Adrenergic, beta / Q000235:genetics / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*; D048490:raf Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D009097:Multienzyme Complexes; C107953:RAC1 protein, human; D011943:Receptors, Adrenergic, beta; D006160:Guanosine Triphosphate; D000242:Cyclic AMP; D048490:raf Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020930:MAP Kinase Kinase Kinases; D020830:rac1 GTP-Binding Protein
keywords: cross-talk; signal transduction
references: Proc Natl Acad Sci U S A. 2005 Oct 4;102(40):14320-5
references: 16176981
references: Proc Natl Acad Sci U S A. 2003 Apr 15;100(8):4445-50
references: 12672969
references: Cell Signal. 2008 Sep;20(9):1592-607
references: 18423978
references: Mol Cell Biol. 1994 Oct;14(10):6696-703
references: 7935389
references: Science. 2000 Oct 13;290(5490):333-7
references: 11030651
references: Nature. 1997 Nov 6;390(6655):88-91
references: 9363896
references: J Biol Chem. 2005 Jan 21;280(3):2055-64
references: 15542607
references: J Biol Chem. 1999 Nov 12;274(46):32565-73
references: 10551809
references: Oncogene. 2013 May 9;32(19):2475-82
references: 22710715
references: Trends Cell Biol. 2002 Jun;12(6):258-66
references: 12074885
references: FEBS J. 2005 Jul;272(14):3491-504
references: 16008550
references: Proc Natl Acad Sci U S A. 2007 Oct 23;104(43):16916-21
references: 17942691
references: Biochem J. 2005 Mar 1;386(Pt 2):201-14
references: 15548136
references: Nat Rev Mol Cell Biol. 2004 Dec;5(12):959-70
references: 15573134
references: Exp Cell Res. 2007 Jul 1;313(11):2504-20
references: 17493609
references: J Biol Chem. 2003 May 23;278(21):19023-31
references: 12654918
references: Science. 1993 Nov 12;262(5136):1069-72
references: 7694367
references: Nat Rev Mol Cell Biol. 2002 Sep;3(9):639-50
references: 12209124
references: Proc Natl Acad Sci U S A. 2003 Feb 4;100(3):940-5
references: 12552097
references: Nature. 1998 Nov 12;396(6707):180-3
references: 9823899
references: Nat Cell Biol. 2010 Dec;12(12):1242-9
references: 21102438
references: Nat Rev Cancer. 2007 Feb;7(2):79-94
references: 17251915
references: Trends Pharmacol Sci. 2007 Dec;28(12):602-7
references: 18001849
references: Proc Natl Acad Sci U S A. 2010 Oct 26;107(43):18622-7
references: 20926745
references: Oncogene. 2007 May 14;26(22):3159-71
references: 17496913
references: Curr Opin Cell Biol. 2005 Apr;17(2):129-34
references: 15780588
references: EMBO J. 1999 Feb 15;18(4):893-903
references: 10022832
references: Front Biosci. 2008 Jan 01;13:1857-65
references: 17981673
references: J Biol Chem. 2010 Feb 19;285(8):5507-21
references: 20007971
references: Science. 2012 Feb 10;335(6069):712-6
references: 22323819
references: Clin Cancer Res. 2012 Mar 1;18(5):1201-6
references: 22186256
references: Nat Med. 2006 Aug;12(8):939-44
references: 16862152
references: Nat Cell Biol. 2000 Sep;2(9):593-600
references: 10980699
references: Nat Rev Cancer. 2002 Feb;2(2):133-42
references: 12635176
references: Oncogene. 2009 Jul 16;28(28):2545-55
references: 19465939
references: Mol Cell Biol. 2002 Sep;22(17):6023-33
references: 12167697
references: J Cell Sci. 2004 Mar 15;117(Pt 8):1301-12
references: 15020670
references: Annu Rev Cell Dev Biol. 2005;21:247-69
references: 16212495
references: Biochem J. 2004 Mar 1;378(Pt 2):335-42
references: 14613483
references: Annu Rev Pharmacol Toxicol. 2010;50:355-75
references: 20055708
references: PLoS One. 2011;6(10):e26250
references: 22022581
references: Mol Cell. 2006 Nov 3;24(3):397-408
references: 17081990
references: J Biol Chem. 2011 Jun 24;286(25):22113-21
references: 21460214
references: Biochim Biophys Acta. 2008 Jan;1784(1):16-26
references: 17996741
references: Oncogene. 2010 Jun 10;29(23):3362-73
references: 20383193
references: Nat Rev Cancer. 2006 Jun;6(6):459-71
references: 16723992
references: Nature. 1994 Jan 6;367(6458):40-6
references: 8107774
references: Oncogene. 2004 Jan 29;23(4):991-9
references: 14647423
references: Am J Physiol Cell Physiol. 2009 Mar;296(3):C453-62
references: 19118163
references: Annu Rev Physiol. 2007;69:483-510
references: 17305471
references: Science. 2009 Nov 27;326(5957):1220-4
references: 19965465
references: J Biol Chem. 2012 Apr 27;287(18):14672-80
references: 22334660
references: Biochem J. 2004 Apr 1;379(Pt 1):1-9
references: 14715081
references: Nat Commun. 2011 Dec 20;2:598
references: 22186894