Experts and Doctors on cyclic amp dependent protein kinases in Durham, North Carolina, United States


Locale: Durham, North Carolina, United States
Topic: cyclic amp dependent protein kinases

Top Publications

  1. Zurita Martinez S, Cardenas M. Tor and cyclic AMP-protein kinase A: two parallel pathways regulating expression of genes required for cell growth. Eukaryot Cell. 2005;4:63-71 pubmed
  2. Chen W, Ren X, Nelson C, Barak L, Chen J, Beachy P, et al. Activity-dependent internalization of smoothened mediated by beta-arrestin 2 and GRK2. Science. 2004;306:2257-60 pubmed
    ..A Smo agonist stimulated and a Smo antagonist (cyclopamine) inhibited both phosphorylation of Smo by GRK2 and interaction of beta-arrestin 2 with Smo. beta-Arrestin 2 and GRK2 are thus potential mediators of signaling by activated Smo. ..
  3. O Meara T, Norton D, Price M, Hay C, Clements M, Nichols C, et al. Interaction of Cryptococcus neoformans Rim101 and protein kinase A regulates capsule. PLoS Pathog. 2010;6:e1000776 pubmed publisher
    ..These results establish a novel mechanism for Rim101 activation and the integration of two conserved signaling cascades in response to host environmental conditions...
  4. Tomfohr J, Lu J, Kepler T. Pathway level analysis of gene expression using singular value decomposition. BMC Bioinformatics. 2005;6:225 pubmed
    ..A web program PLAGE (Pathway Level Analysis of Gene Expression) for performing the kinds of analyses described here is accessible at ..
  5. Wooldridge A, Fortner C, Lontay B, Akimoto T, Neppl R, Facemire C, et al. Deletion of the protein kinase A/protein kinase G target SMTNL1 promotes an exercise-adapted phenotype in vascular smooth muscle. J Biol Chem. 2008;283:11850-9 pubmed publisher
    ..Our findings suggest roles for SMTNL1 in cGMP/cAMP-mediated adaptations to exercise through mechanisms involving direct modulation of contractile activity. ..
  6. Fredericks Z, Pitcher J, Lefkowitz R. Identification of the G protein-coupled receptor kinase phosphorylation sites in the human beta2-adrenergic receptor. J Biol Chem. 1996;271:13796-803 pubmed
    ..The location of multiple GRK2 and GRK5 phosphoacceptor sites at the extreme carboxyl terminus of the beta2AR is highly reminiscent of GRK1-mediated phosphorylation of rhodopsin. ..
  7. Arriza J, Dawson T, Simerly R, Martin L, Caron M, Snyder S, et al. The G-protein-coupled receptor kinases beta ARK1 and beta ARK2 are widely distributed at synapses in rat brain. J Neurosci. 1992;12:4045-55 pubmed
    ..The beta ARK isozymes have a regional and subcellular distribution consistent with a general role in the desensitization of synaptic receptors. ..
  8. Tong H, Bernstein D, Murphy E, Steenbergen C. The role of beta-adrenergic receptor signaling in cardioprotection. FASEB J. 2005;19:983-5 pubmed
    ..These data show an important role for beta2-AR in cardioprotection and support the novel hypothesis that preconditioning involves switching of beta2-AR coupling from Gs to Gi. ..
  9. Martin N, Whalen E, Zamah M, Pierce K, Lefkowitz R. PKA-mediated phosphorylation of the beta1-adrenergic receptor promotes Gs/Gi switching. Cell Signal. 2004;16:1397-403 pubmed
    ..These results strongly support the hypothesis that the beta(1)-AR, like the beta(2)-AR, can undergo PKA-dependent "G(s)/G(i) switching". ..

More Information


  1. Freeman J, Gonzalo P, Pitcher J, Claing A, Lavergne J, Reboud J, et al. Beta 2-adrenergic receptor stimulated, G protein-coupled receptor kinase 2 mediated, phosphorylation of ribosomal protein P2. Biochemistry. 2002;41:12850-7 pubmed
  2. Koch W, Rockman H, Samama P, Hamilton R, Bond R, Milano C, et al. Cardiac function in mice overexpressing the beta-adrenergic receptor kinase or a beta ARK inhibitor. Science. 1995;268:1350-3 pubmed
    ..Because increased amounts of beta ARK1 and diminished cardiac beta-adrenergic responsiveness characterize heart failure, these animals may provide experimental models to study the role of beta ARK in heart disease. ..
  3. Premont R, Claing A, Vitale N, Freeman J, Pitcher J, Patton W, et al. beta2-Adrenergic receptor regulation by GIT1, a G protein-coupled receptor kinase-associated ADP ribosylation factor GTPase-activating protein. Proc Natl Acad Sci U S A. 1998;95:14082-7 pubmed
    ..Moreover, they provide a mechanism for integration of receptor activation and endocytosis through regulation of ARF protein activation by GRK-mediated recruitment of the GIT1 ARF GAP to the plasma membrane. ..
  4. Perrino C, Naga Prasad S, Patel M, Wolf M, Rockman H. Targeted inhibition of beta-adrenergic receptor kinase-1-associated phosphoinositide-3 kinase activity preserves beta-adrenergic receptor signaling and prolongs survival in heart failure induced by calsequestrin overexpression. J Am Coll Cardiol. 2005;45:1862-70 pubmed
    ..Desensitization and down-regulation of beta-adrenergic receptors (betaARs) are prominent features of heart failure largely mediated by increased levels of betaAR kinase-1 (betaARK1)...
  5. Wilbanks A, Fralish G, Kirby M, Barak L, Li Y, Caron M. Beta-arrestin 2 regulates zebrafish development through the hedgehog signaling pathway. Science. 2004;306:2264-7 pubmed
    ..These results suggest that a functional interaction between beta-arrestin 2 and Smoothened may be critical to regulate Hh signaling in zebrafish development. ..
  6. Pan X, Heitman J. Protein kinase A operates a molecular switch that governs yeast pseudohyphal differentiation. Mol Cell Biol. 2002;22:3981-93 pubmed
    ..Our studies illustrate in molecular detail how protein kinase A combinatorially effects a key developmental switch. Similar mechanisms may operate in pathogenic fungi and more complex multicellular eukaryotic organisms. ..
  7. Connor J, Weiser D, Li S, Hallenbeck J, Shenolikar S. Growth arrest and DNA damage-inducible protein GADD34 assembles a novel signaling complex containing protein phosphatase 1 and inhibitor 1. Mol Cell Biol. 2001;21:6841-50 pubmed publisher
    ..These studies suggested that modification of the I-1/GADD34/PP1 signaling complex regulates the initiation of protein translation in mammalian tissues...
  8. Hu L, Chen W, Premont R, Cong M, Lefkowitz R. G protein-coupled receptor kinase 5 regulates beta 1-adrenergic receptor association with PSD-95. J Biol Chem. 2002;277:1607-13 pubmed
    ..Regulation of protein association through receptor phosphorylation may be a general mechanism used by G protein-coupled receptors that associate via PDZ domain-mediated protein/protein interactions. ..
  9. Jaber M, Koch W, Rockman H, Smith B, Bond R, Sulik K, et al. Essential role of beta-adrenergic receptor kinase 1 in cardiac development and function. Proc Natl Acad Sci U S A. 1996;93:12974-9 pubmed
  10. Misra U, Pizzo S. Coordinate regulation of forskolin-induced cellular proliferation in macrophages by protein kinase A/cAMP-response element-binding protein (CREB) and Epac1-Rap1 signaling: effects of silencing CREB gene expression on Akt activation. J Biol Chem. 2005;280:38276-89 pubmed
    ..We conclude that forskolin mediates cellular proliferation via cAMP-dependent activation of both PKA and Epac. ..
  11. Pan X, Heitman J. Cyclic AMP-dependent protein kinase regulates pseudohyphal differentiation in Saccharomyces cerevisiae. Mol Cell Biol. 1999;19:4874-87 pubmed
  12. Ward M, Garrett S. Suppression of a yeast cyclic AMP-dependent protein kinase defect by overexpression of SOK1, a yeast gene exhibiting sequence similarity to a developmentally regulated mouse gene. Mol Cell Biol. 1994;14:5619-27 pubmed
  13. Weiser D, Sikes S, Li S, Shenolikar S. The inhibitor-1 C terminus facilitates hormonal regulation of cellular protein phosphatase-1: functional implications for inhibitor-1 isoforms. J Biol Chem. 2004;279:48904-14 pubmed
    ..This study demonstrates that multiple domains in I-1 target cellular PP1 complexes and establishes I-1 as a cellular regulator of eIF2alpha phosphorylation. ..
  14. Esposito G, Rapacciuolo A, Naga Prasad S, Takaoka H, Thomas S, Koch W, et al. Genetic alterations that inhibit in vivo pressure-overload hypertrophy prevent cardiac dysfunction despite increased wall stress. Circulation. 2002;105:85-92 pubmed
    ..These data suggest that under conditions of pressure overload, the development of cardiac hypertrophy and normalization of wall stress may not be necessary to preserve cardiac function, as previously hypothesized. ..
  15. Williams M, Hata J, Schroder J, Rampersaud E, Petrofski J, Jakoi A, et al. Targeted beta-adrenergic receptor kinase (betaARK1) inhibition by gene transfer in failing human hearts. Circulation. 2004;109:1590-3 pubmed
    ..Thus, betaARK1 inhibition may represent a therapeutic strategy for human HF. ..
  16. Keys J, Greene E, Cooper C, Naga Prasad S, Rockman H, Koch W. Cardiac hypertrophy and altered beta-adrenergic signaling in transgenic mice that express the amino terminus of beta-ARK1. Am J Physiol Heart Circ Physiol. 2003;285:H2201-11 pubmed
    ..Thus the amino terminus of beta-ARK1 appears to be critical for normal beta-AR regulation in vivo, which further supports the hypothesis that beta-ARK1 plays a key role in normal and compromised cardiac GPCR signaling. ..
  17. Perry S, Baillie G, Kohout T, McPhee I, Magiera M, Ang K, et al. Targeting of cyclic AMP degradation to beta 2-adrenergic receptors by beta-arrestins. Science. 2002;298:834-6 pubmed
  18. Cong M, Perry S, Lin F, Fraser I, Hu L, Chen W, et al. Regulation of membrane targeting of the G protein-coupled receptor kinase 2 by protein kinase A and its anchoring protein AKAP79. J Biol Chem. 2001;276:15192-9 pubmed
    ..Agonist-stimulated PKA-mediated phosphorylation of GRK2 may represent a mechanism for enhancing receptor phosphorylation and desensitization. ..
  19. Lohse M, Benovic J, Codina J, Caron M, Lefkowitz R. beta-Arrestin: a protein that regulates beta-adrenergic receptor function. Science. 1990;248:1547-50 pubmed
    ..It is proposed that beta-arrestin in concert with beta ARK effects homologous desensitization of beta-adrenergic receptors. ..
  20. Esposito G, Santana L, Dilly K, Cruz J, Mao L, Lederer W, et al. Cellular and functional defects in a mouse model of heart failure. Am J Physiol Heart Circ Physiol. 2000;279:H3101-12 pubmed
    ..Furthermore, this work suggests that the inhibition of betaARK1 action may prove an effective therapy for heart failure...
  21. Ribar T, Rodriguiz R, Khiroug L, Wetsel W, Augustine G, Means A. Cerebellar defects in Ca2+/calmodulin kinase IV-deficient mice. J Neurosci. 2000;20:RC107 pubmed
    ..Together, these findings demonstrate that CaMKIV plays key roles in the function and development of the cerebellum. ..
  22. Pan X, Heitman J. Sok2 regulates yeast pseudohyphal differentiation via a transcription factor cascade that regulates cell-cell adhesion. Mol Cell Biol. 2000;20:8364-72 pubmed
    ..Finally, these studies illustrate how mother-daughter cell adhesion can be accomplished by two distinct mechanisms: one involving Flo11 and the other involving regulation of the endochitinase Cts1 and the endoglucanase Egt2 by Swi5. ..
  23. Yang Y, Calakos N. Acute in vivo genetic rescue demonstrates that phosphorylation of RIM1alpha serine 413 is not required for mossy fiber long-term potentiation. J Neurosci. 2010;30:2542-6 pubmed publisher
    ..Together, these results provide insights into the mechanism of mossy fiber LTP and demonstrate a useful acute approach to genetically manipulate mossy fiber synapses in the mature brain. ..
  24. Freedman N, Ament A, Oppermann M, Stoffel R, Exum S, Lefkowitz R. Phosphorylation and desensitization of human endothelin A and B receptors. Evidence for G protein-coupled receptor kinase specificity. J Biol Chem. 1997;272:17734-43 pubmed
    ..We propose that because of its affinity for ET-Rs demonstrated by co-immunoprecipitation, GRK2 is the most likely of the GRKs to initiate ET-R desensitization. ..
  25. Zennadi R, Hines P, De Castro L, Cartron J, Parise L, Telen M. Epinephrine acts through erythroid signaling pathways to activate sickle cell adhesion to endothelium via LW-alphavbeta3 interactions. Blood. 2004;104:3774-81 pubmed
    ..These data suggest that adrenergic hormones such as epinephrine may initiate or exacerbate vaso-occlusion and thus contribute to the association of vaso-occlusive events with physiologic stress. ..
  26. Liu S, Premont R, Kontos C, Zhu S, Rockey D. A crucial role for GRK2 in regulation of endothelial cell nitric oxide synthase function in portal hypertension. Nat Med. 2005;11:952-8 pubmed
    ..Thus, an important mechanism underlying impaired activity of eNOS in injured sinusoidal endothelial cells is defective phosphorylation of Akt caused by overexpression of GRK2 after injury. ..
  27. Harashima T, Anderson S, Yates J, Heitman J. The kelch proteins Gpb1 and Gpb2 inhibit Ras activity via association with the yeast RasGAP neurofibromin homologs Ira1 and Ira2. Mol Cell. 2006;22:819-30 pubmed
    ..Because the Gpb1/2 binding domain on Ira1/2 is conserved in the human neurofibromin protein, an analogous signaling network may contribute to the neoplastic development of neurofibromatosis type 1. ..
  28. Hartley A, Ward M, Garrett S. The Yak1 protein kinase of Saccharomyces cerevisiae moderates thermotolerance and inhibits growth by an Sch9 protein kinase-independent mechanism. Genetics. 1994;136:465-74 pubmed
    ..These results, for the first time, associate a phenotype, other than suppression of the A kinase growth defect, with the loss of Yak1 activity and argue a broader role for the Yak1 kinase in cell growth. ..
  29. Misra U, Pizzo S. Epac1-induced cellular proliferation in prostate cancer cells is mediated by B-Raf/ERK and mTOR signaling cascades. J Cell Biochem. 2009;108:998-1011 pubmed publisher
    ..We conclude that B-Raf/ERK and mTOR signaling play an essential role in cAMP-dependent, but PKA-independent, proliferation of cancer cells. ..
  30. Koch W, Rockman H. Exploring the role of the beta-adrenergic receptor kinase in cardiac disease using gene-targeted mice. Trends Cardiovasc Med. 1999;9:77-81 pubmed
    ..Interrupting this process may provide novel therapeutic strategies in the treatment of human heart failure. ..
  31. Hildreth K, Wu J, Barak L, Exum S, Kim L, Peppel K, et al. Phosphorylation of the platelet-derived growth factor receptor-beta by G protein-coupled receptor kinase-2 reduces receptor signaling and interaction with the Na(+)/H(+) exchanger regulatory factor. J Biol Chem. 2004;279:41775-82 pubmed
    ..Furthermore, this desensitization appears to involve GRK2-mediated phosphorylation of PDGFRbeta Ser(1104), with consequent dissociation of the PDGFRbeta from NHERF. ..
  32. Ward M, Gimeno C, Fink G, Garrett S. SOK2 may regulate cyclic AMP-dependent protein kinase-stimulated growth and pseudohyphal development by repressing transcription. Mol Cell Biol. 1995;15:6854-63 pubmed
    ..Thus, the product of SOK2 may act downstream of PKA to regulate the expression of genes important in growth and development. ..
  33. Lorenz W, Inglese J, Palczewski K, Onorato J, Caron M, Lefkowitz R. The receptor kinase family: primary structure of rhodopsin kinase reveals similarities to the beta-adrenergic receptor kinase. Proc Natl Acad Sci U S A. 1991;88:8715-9 pubmed
  34. Pitcher J, Tesmer J, Freeman J, Capel W, Stone W, Lefkowitz R. Feedback inhibition of G protein-coupled receptor kinase 2 (GRK2) activity by extracellular signal-regulated kinases. J Biol Chem. 1999;274:34531-4 pubmed
  35. Wu J, Goswami R, Kim L, Miller W, Peppel K, Freedman N. The platelet-derived growth factor receptor-beta phosphorylates and activates G protein-coupled receptor kinase-2. A mechanism for feedback inhibition. J Biol Chem. 2005;280:31027-35 pubmed
    ..We conclude that the activated PDGFRbeta itself phosphorylates GRK2 tyrosyl residues and thereby activates GRK2, which then serine-phosphorylates and desensitizes the PDGFRbeta. ..
  36. Matsuoka Y, Hughes C, Bennett V. Adducin regulation. Definition of the calmodulin-binding domain and sites of phosphorylation by protein kinases A and C. J Biol Chem. 1996;271:25157-66 pubmed
    ..These findings suggest a complex reciprocal relationship between regulation of adducin function by calmodulin binding and phosphorylation by PKA and PKC. ..
  37. Mukhopadhyay S, Das S, Williams E, Moore D, Jones J, Zahm D, et al. Lipopolysaccharide and cyclic AMP regulation of CB(2) cannabinoid receptor levels in rat brain and mouse RAW 264.7 macrophages. J Neuroimmunol. 2006;181:82-92 pubmed
    ..Forskolin or dibutyryl cyclic AMP increased CB(2) receptor immunoreactivity, suggesting the involvement of the cyclic AMP-protein kinase A-Cyclic AMP response element pathway in the regulation of CB(2) receptor levels. ..
  38. Attramadal H, Arriza J, Aoki C, Dawson T, Codina J, Kwatra M, et al. Beta-arrestin2, a novel member of the arrestin/beta-arrestin gene family. J Biol Chem. 1992;267:17882-90 pubmed
    ..Furthermore, immunoelectron microscopy shows that the beta-arrestins are appropriately situated at postsynaptic sites to act in concert with beta ARK to regulate G protein-coupled neurotransmitter receptors. ..
  39. Harding V, Jones L, Lefkowitz R, Koch W, Rockman H. Cardiac beta ARK1 inhibition prolongs survival and augments beta blocker therapy in a mouse model of severe heart failure. Proc Natl Acad Sci U S A. 2001;98:5809-14 pubmed
    ..These data demonstrate a significant synergy between an established heart-failure treatment and the strategy of betaARK1 inhibition. ..
  40. Smith A, Ward M, Garrett S. Yeast PKA represses Msn2p/Msn4p-dependent gene expression to regulate growth, stress response and glycogen accumulation. EMBO J. 1998;17:3556-64 pubmed
    ..These results suggest that Msn2p/Msn4p-dependent gene expression may account for all, or at least most, of the pleiotropic effects of yeast PKA, including growth regulation, response to stress and carbohydrate store accumulation. ..
  41. Naga Prasad S, Jayatilleke A, Madamanchi A, Rockman H. Protein kinase activity of phosphoinositide 3-kinase regulates beta-adrenergic receptor endocytosis. Nat Cell Biol. 2005;7:785-96 pubmed
    ..These studies demonstrate a previously unknown role for the protein phosphorylation activity of PI(3)K in betaAR internalization and identify non-muscle tropomyosin as a cellular substrate for protein kinase activity of PI(3)K. ..
  42. Hagen S, Kondyra A, Grocott H, El Moalem H, Bainbridge D, Mathew J, et al. Cardiopulmonary bypass decreases G protein-coupled receptor kinase activity and expression in human peripheral blood mononuclear cells. Anesthesiology. 2003;98:343-8 pubmed
    ..The significance of the variable recovery of GRKs after CPB and their potential role as a marker of clinical outcome deserves further investigation. ..
  43. Naga Prasad S, Laporte S, Chamberlain D, Caron M, Barak L, Rockman H. Phosphoinositide 3-kinase regulates beta2-adrenergic receptor endocytosis by AP-2 recruitment to the receptor/beta-arrestin complex. J Cell Biol. 2002;158:563-75 pubmed
  44. Benovic J, DeBlasi A, Stone W, Caron M, Lefkowitz R. Beta-adrenergic receptor kinase: primary structure delineates a multigene family. Science. 1989;246:235-40 pubmed
    ..RNA blot analysis revealed a messenger RNA of four kilobases with highest amounts in brain and spleen. Genomic DNA blot analysis also suggests that beta-ARK may be the first sequenced member of a multigene family of receptor kinases. ..
  45. D Souza C, Hagen F, Boekhout T, Cox G, Heitman J. Investigation of the basis of virulence in serotype A strains of Cryptococcus neoformans from apparently immunocompetent individuals. Curr Genet. 2004;46:92-102 pubmed
    ..Taken together, our findings indicate that the ability of these clinical isolates to infect apparently normal individuals may be attributable to mutations other than pkr1 and/or underlying immune system impairment in patients...
  46. Marion S, Weiner D, Caron M. RNA editing induces variation in desensitization and trafficking of 5-hydroxytryptamine 2c receptor isoforms. J Biol Chem. 2004;279:2945-54 pubmed
    ..Thus the ultimate physiological output of constitutively active receptors may be determined not only by their agonist-independent activity but also by their interactions with GRKs and betaarrestin. ..
  47. Gesty Palmer D, Chen M, Reiter E, Ahn S, Nelson C, Wang S, et al. Distinct beta-arrestin- and G protein-dependent pathways for parathyroid hormone receptor-stimulated ERK1/2 activation. J Biol Chem. 2006;281:10856-64 pubmed
    ..These findings imply the existence of distinct active conformations of the hPTH1R responsible for the two pathways, which can be stimulated by unique ligands. Such ligands may have distinct and valuable therapeutic properties. ..
  48. Naga Prasad S, Barak L, Rapacciuolo A, Caron M, Rockman H. Agonist-dependent recruitment of phosphoinositide 3-kinase to the membrane by beta-adrenergic receptor kinase 1. A role in receptor sequestration. J Biol Chem. 2001;276:18953-9 pubmed