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ADRBK1  -  adrenergic, beta, receptor kinase 1

Bos taurus

 
 
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Disease relevance of ADRBK1

 

High impact information on ADRBK1

 

Biological context of ADRBK1

  • Because activation of GRK2 may involve phosphorylation of its N-terminal tyrosines by c-Src, we tested whether the PDGFRbeta itself could tyrosine-phosphorylate and activate GRK2 [7].
  • A previously described method that conferred analog sensitivity on various kinases, by introducing a space-creating mutation in the conserved active site, failed when applied to GRK2 because the corresponding mutation (L271G) rendered the mutant kinase (GRK2-as1) catalytically inactive [8].
  • This direct stimulatory action of intrinsic domains on GRK2 activity does not add to the effect of other regulators, such as Gbetagamma subunits, and strongly suggests the existence of some mode of autoregulation [9].
  • The crystal structure of the GRK2-Gbetagamma complex revealed that the domains of GRK2 are intimately associated and left open the possibility for allosteric regulation by Gbetagamma [10].
  • These proteins share a high degree of sequence homology with the bovine beta-adrenergic receptor kinase [11].
 

Anatomical context of ADRBK1

  • Treatment of Cos-7 cells transiently overexpressing GRK2 with a beta-receptor agonist promotes a 3-fold increase in plasma membrane-associated GRK2 [6].
 

Associations of ADRBK1 with chemical compounds

  • Furthermore, both PDGFRbeta-mediated GRK2 tyrosyl phosphorylation and GRK2-mediated PDGFRbeta seryl phosphorylation were reduced approximately 50% in intact cells by mutation to phenylalanine of three tyrosines in the N-terminal domain of GRK2 [7].
  • Effect of G protein-coupled receptor kinase 2 on the sensitivity of M4 muscarinic acetylcholine receptors to agonist-induced internalization and desensitization in NG108-15 cells [12].
  • Exposure of the cells to hyperosmolar sucrose (0.6 M) almost completely blocked agonist-induced receptor internalization in both control and GRK2-overexpressing cells [12].
  • Overexpression of a dominant negative form of GRK2 had more modest effects, reducing the rate constant for endocytosis (from 0.11 to 0.07 min(-1)) and increasing the EC50 for carbachol stimulation of internalization (from 8 to 17 microM) [12].
  • In the case of the beta-adrenergic receptor kinase (betaARK), PH domain-mediated binding of two ligands, the betagamma subunits of heterotrimeric G proteins (Gbetagamma) and phosphatidylinositol 4,5-bisphosphate (PIP2), has been shown to be required for the kinase function [13].
 

Physical interactions of ADRBK1

  • Galphaq forms an effector-like interaction with the GRK2 regulator of G protein signaling (RGS) homology domain that is distinct from and does not overlap with that used to bind RGS proteins such as RGS4 [14].
  • The findings that the CC region of GRKs interact only with the light-activated but not the non-activated rhodopsin and that the N-terminal domain of GRK-2 interacts with rhodopsin in a light-independent manner suggest that the CC region is responsible for the recognition of activated GPCRs in the canonical model [15].
 

Enzymatic interactions of ADRBK1

  • The beta-adrenergic receptor kinase (beta-ARK) is a recently discovered enzyme which specifically phosphorylates the agonist-occupied form of the beta-adrenergic receptor (beta-AR) as well as the light-bleached form of rhodopsin. beta-ARK is present in a wide variety of mammalian tissues [16].
 

Regulatory relationships of ADRBK1

  • We report that kinase activity toward either GPCR (rhodopsin) or a synthetic peptide substrate is enhanced in the presence of GST-GRK2 fusion proteins or peptides corresponding to either N- or C-terminal sequences of GRK2 [9].
 

Other interactions of ADRBK1

 

Analytical, diagnostic and therapeutic context of ADRBK1

References

  1. Interactions of phosducin with defined G protein beta gamma-subunits. Müller, S., Straub, A., Schröder, S., Bauer, P.H., Lohse, M.J. J. Biol. Chem. (1996) [Pubmed]
  2. Betagamma subunits mediate the NPY enhancement of ATP-stimulated inositol phosphate formation. Li, X., Ikezu, T., Hexum, T.D. Peptides (2004) [Pubmed]
  3. Expression and characterization of two beta-adrenergic receptor kinase isoforms using the baculovirus expression system. Kim, C.M., Dion, S.B., Onorato, J.J., Benovic, J.L. Receptor (1993) [Pubmed]
  4. Light-dependent phosphorylation of rhodopsin by beta-adrenergic receptor kinase. Benovic, J.L., Mayor, F., Somers, R.L., Caron, M.G., Lefkowitz, R.J. Nature (1986) [Pubmed]
  5. Beta-adrenergic receptor kinase: primary structure delineates a multigene family. Benovic, J.L., DeBlasi, A., Stone, W.C., Caron, M.G., Lefkowitz, R.J. Science (1989) [Pubmed]
  6. Receptor and G betagamma isoform-specific interactions with G protein-coupled receptor kinases. Daaka, Y., Pitcher, J.A., Richardson, M., Stoffel, R.H., Robishaw, J.D., Lefkowitz, R.J. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  7. The platelet-derived growth factor receptor-beta phosphorylates and activates G protein-coupled receptor kinase-2. A mechanism for feedback inhibition. Wu, J.H., Goswami, R., Kim, L.K., Miller, W.E., Peppel, K., Freedman, N.J. J. Biol. Chem. (2005) [Pubmed]
  8. Chemical genetic engineering of G protein-coupled receptor kinase 2. Kenski, D.M., Zhang, C., von Zastrow, M., Shokat, K.M. J. Biol. Chem. (2005) [Pubmed]
  9. Involvement of intramolecular interactions in the regulation of G protein-coupled receptor kinase 2. Sarnago, S., Roca, R., de Blasi, A., Valencia, A., Mayor, F., Murga, C. Mol. Pharmacol. (2003) [Pubmed]
  10. The role of G beta gamma and domain interfaces in the activation of G protein-coupled receptor kinase 2. Lodowski, D.T., Barnhill, J.F., Pyskadlo, R.M., Ghirlando, R., Sterne-Marr, R., Tesmer, J.J. Biochemistry (2005) [Pubmed]
  11. Isolation of Drosophila genes encoding G protein-coupled receptor kinases. Cassill, J.A., Whitney, M., Joazeiro, C.A., Becker, A., Zuker, C.S. Proc. Natl. Acad. Sci. U.S.A. (1991) [Pubmed]
  12. Effect of G protein-coupled receptor kinase 2 on the sensitivity of M4 muscarinic acetylcholine receptors to agonist-induced internalization and desensitization in NG108-15 cells. Holroyd, E.W., Szekeres, P.G., Whittaker, R.D., Kelly, E., Edwardson, J.M. J. Neurochem. (1999) [Pubmed]
  13. Binding of multiple ligands to pleckstrin homology domain regulates membrane translocation and enzyme activity of beta-adrenergic receptor kinase. Touhara, K. FEBS Lett. (1997) [Pubmed]
  14. Snapshot of activated G proteins at the membrane: the Galphaq-GRK2-Gbetagamma complex. Tesmer, V.M., Kawano, T., Shankaranarayanan, A., Kozasa, T., Tesmer, J.J. Science (2005) [Pubmed]
  15. Involvement of the C-terminal proline-rich motif of G protein-coupled receptor kinases in recognition of activated rhodopsin. Gan, X., Ma, Z., Deng, N., Wang, J., Ding, J., Li, L. J. Biol. Chem. (2004) [Pubmed]
  16. Purification and characterization of the beta-adrenergic receptor kinase. Benovic, J.L., Mayor, F., Staniszewski, C., Lefkowitz, R.J., Caron, M.G. J. Biol. Chem. (1987) [Pubmed]
  17. The receptor kinase family: primary structure of rhodopsin kinase reveals similarities to the beta-adrenergic receptor kinase. Lorenz, W., Inglese, J., Palczewski, K., Onorato, J.J., Caron, M.G., Lefkowitz, R.J. Proc. Natl. Acad. Sci. U.S.A. (1991) [Pubmed]
  18. G protein-coupled receptor Kinase 2/G alpha q/11 interaction. A novel surface on a regulator of G protein signaling homology domain for binding G alpha subunits. Sterne-Marr, R., Tesmer, J.J., Day, P.W., Stracquatanio, R.P., Cilente, J.A., O'Connor, K.E., Pronin, A.N., Benovic, J.L., Wedegaertner, P.B. J. Biol. Chem. (2003) [Pubmed]
  19. Purification, crystallization and preliminary X-ray diffraction studies of a complex between G protein-coupled receptor kinase 2 and Gbeta1gamma2. Lodowski, D.T., Barnhill, J.F., Pitcher, J.A., Capel, W.D., Lefkowitz, R.J., Tesmer, J.J. Acta Crystallogr. D Biol. Crystallogr. (2003) [Pubmed]
 
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