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Targeting G protein-coupled receptor kinases to their receptor substrates

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Conclusion

Membrane association is essential for GRK function and because of this the GRKs have evolved complex regulatory mechanisms for associating with the membrane. Although the GRKs are highly homologous, each kinase utilizes a distinct mechanism for associating with the membrane, which makes it unique within the family. Initially, the carboxyl terminus of the GRKs was identified as the “membrane association domain” but recent evidence suggests that the amino terminus may also play a critical role in localizing the kinases to the membrane (Murga et al., 1996; Pitcher et al, 1996). It is within these two domains that the GRKs are most variable at the amino acid level. The GRKS exhibit an absolute requirement for phospholipids not only for association with the membrane but also for activity. There are differences in preference and binding sites for the phospholipids within the GRK family, which may reflect differential targeting of the GRKs to G protein-coupled receptors situated in different lipid environments. There are hundreds of G protein-coupled receptors and only six known GRKs. All the GRKs appear to phosphorylate the same receptor substrates in vitro (Sterne-Marr & Benovic, 1995; Premont et al., 1995). Receptor specificity, in a cellular

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References

  1. Ambrose, C., James, M., Barnes, G., Lin, C., Bates, G., Altherr, M., Duyao, M., Groot, N., Church, D., Wasmuth, J.J., Lehrach, H., Housman, D., Buckler, A., Gusells, J.F., MacDonald, M.E. 1992. A novel G protein-coupled receptor kinase gene cloned from 4pl6.3. Hum. Mol Genet. 1:697–703

  2. Benovic, J.L., De Blasi, A., Stone, W.C., Caron, M.G., Lefkowitz, R.J. 1989. β-Adrenergic receptor kinase: Primary structure delineates a multigene family. Science 246:235–240

  3. Benovic, J.L., Onorato, J.J., Arriza, J.L., Stone, W.C., Lohse, M., Jenkins, N.A., Gilbert, D.J., Copeland, N.G., Caron, M.G., Lefkowitz, R.J. 1991. Cloning, expression, and chromosomal localization of the β-adrenergic receptor kinase 2: A new member of the receptor kinase family. J. Biol. Cham. 266:14939–14946

  4. Benovic, J.L., Gomez, J. 1993. Molecular cloning and expression of GRK6: A new member of the G protein-coupled receptor kinase family. J. Biol. Chem. 268:19521–19527

  5. Boekhoff, I., Inglese, J., Schleicher, S., Koch, W.J., Lefkowitz, R.J., Breer, H. 1994. Olfactory desensitization requires membrane targeting of receptor kinase mediated by βγ-subunits of heterotrimeric G proteins. J. Biol. Chem. 269:37–40

  6. Chen, C.-Y., Dion, S.D., Kim, CM., Benovic, J.L. 1993. β-Adrenergic receptor kinase: Agonist-dependent receptor binding promotes kinase activation. J. Biol. Chem. 268:7825–7831

  7. Cohen, G.B., Ren, R., Baltimore, D. 1995. Modular binding domains in signal transduction proteins. Cell 80:237–248

  8. Daaka, Y., Pitcher, J.A., Richardson, M., Stoffel, R.H., Robishaw, J.D., Lefkowitz, R.J. 1997. Receptor and Gβγ isoform specific interactions with G protein-coupled receptor kinases. Proc. Natl. Acad. Sci. USA (in press)

  9. DebBurman, S.K., Ptasienski, J., Boetticher, E., Lomasney, J.W., Benovic, J.L., Hosey, M.M. 1995. Lipid-mediated regulation of G protein-coupled receptor kinases 2 and 3. J. Biol. Chem. 270:5742–5747

  10. DebBurman, S.K., Ptasienski, J., Benovic, J.L., Hosey, M.M. 1996. G protein-coupled receptor kinase GRK2 is a phospholipid-dependent enzyme that can be conditionally activated by G protein βγ subunits. J. Biol. Chem. 271:22552–22562

  11. Degtyarev, M.Y., Spiegel, A.M., Jones, T.L. 1993. Increased palmitoylation of the Gs protein alpha subunit after activation by the beta-adrenergic receptor or cholera toxin. J. Biol. Chem. 268:23769–23772

  12. Freedman, N.J., Lefkowitz, R.J. 1996. Recent Prog. Horm. Res. 51:319–353

  13. Garcia-Higuera, I., Penela, P., Murga, C., Egea, G., Bonay, P., Benovic, J.L., Mayor, F. 1994. Association of the regulatory β-adrenergic receptor kinase with rat liver microsomal membranes. J. Biol. Chem. 269:1348–1355

  14. Haga, K., Haga, T. 1992. Activation by G protein beta gamma subunits of agonistor light-dependent phosphorylation of muscarinic acetylcholine receptors and rhodopsin. J. Biol. Chem. 267:2222–2227

  15. Haga, T., Haga, K., Kameyama, K. 1994. G protein-coupled receptor kinases. J. Neurochem. 63:400–412

  16. Haribabu, B., Snyderman, R. 1993. Identification of additional members of the human G protein-coupled receptor kinase family. Proc. Natl. Acad. Sci. USA 90:9398–9402

  17. Harlan, J.E., Hajduk, P.J., Yoon, H.S., Fesik, S.W. 1994. Pleckstrin homology domains bind to phosphatidylinositol-4,5-bisphosphate. Nature 371:168–170

  18. Inglese, J., Glickman, J.F., Lorenz, W., Caron, M.G., Lefkowitz, R.J. 1992a. Isoprenylation of a protein kinase: Requirement of farnesylation/α-carboxyl methylation for full enzymatic activity of rhodopsin kinase. J. Biol. Chem. 267:1422–1425

  19. Inglese, J., Koch, W.J., Caron, M.G., Lefkowitz, R.J. 1992b. Isoprenylation in regulation of signal transduction by G proteincoupled receptor kinases. Nature 359:147–150

  20. Inglese, J., Freedman, N.J., Koch, W.J., Lefkowitz, R.J. 1993. Structure and mechanism of the G protein-coupled receptor kinases. J. Biol. Chem. 268:23735–23738

  21. Kennedy, M.E., Limbird, L.E. 1994. Palmitoylation of the alpha 2-Aadrenergic receptor. Analysis of the sequence requirements for and the dynamic properties of alpha 2A-adrenergic receptor palmitoylation. J. Biol. Chem. 269:31915–31922

  22. Kim, C.M., Dion, S.B., Benovic, J.L. 1993. Mechanism of β-adrenergic receptor kinase activation by G proteins. J. Biol. Chem. 268:15412–15418

  23. Koch, W.J., Inglese, J., Stone, W.C., Lefkowitz, R.J. 1993. The binding site for the βγ subunits of heterotrimeric G proteins on the β-adrenergic receptor kinase. J. Biol. Chem. 268:8256–8260

  24. Kunapuli, P., Benovic, J.L. 1993. Cloning and expression of GRK5: A member of the G protein-coupled receptor kinase family. Proc. Natl. Acad. Sci. USA 90:5588–5592

  25. Kunapuli, P., Gurevich, V.V., Benovic, J.L. 1993. Phospholipidstimulated autophosphorylation activates the G protein-coupled receptor kinase GRK5. J. Biol. Chem. 269:10209–10212

  26. Levis, M.J., Bourne, H.R. 1992. Activation of Gs in intact cells alters its abundance, rate of degradation and membrane avidity. J. Cell Biol. 119:1297–1307

  27. Linder, M.E., Middleton, P., Hepler, J.R., Tausig, R., Gilman, A.G., Mumby, S.M. 1993. Lipid modifications of G proteins: α subunits are palmitoylated. Proc. Natl. Acad. Sci. USA 90:3675–3679

  28. Lorenz, W., Inglese, J., Palczewski, K., Onorato, J.J., Caron, M.G., Lefkowitz, R.J. 1991. The receptor kinase family: Primary structure of rhodopsin kinase reveals similarities to the β-adrenergic receptor kinase. Proc. Natl. Acad. Sci. USA 88:8715–8719

  29. Mouillac, B., Caron, M., Bonin, H., Dennis, M., Bouvier, M. 1992. Agonist-modulated palmitoylation of beta 2-adrenergic receptor in Sf9 cells. J. Biol. Chem. 267:21733–21737

  30. Murga, C., Ruiz-Gomez, A., Garcia-Higuera, I., Kim, CM., Benovic, J.L., Mayor, F. 1996. High avinity binding of β-adrenergic receptor kinase to microsomal membranes. J. Biol. Chem. 270:985–994

  31. Onorato, J.J., Gillis, M.E., Liu, Y., Benovic, J.L., Ruoho, A.E. 1995. The β-adrenergic receptor kinase (GRK2) is regulated by phospholipids. J. Biol. Chem. 270:21346–21353

  32. Palczewski, K., Buczylko, J., Kaplan, M.W., Polans, A.S., Crabb, J.W. 1991. Mechanism of rhodopsin kinase activation. J. Biol. Chem. 266:12949–12955

  33. Palczewski, K., Buczylko, J., Van Hooser, P., Carr, S.A., Huddleston, M.J., Crabb, J.W. 1992. Identification of the autophosphorylation sites in rhodopsin kinase. J. Biol. Chem. 267:18991–18998

  34. Palczewski, K., Buczylko, J., Lebioda, L., Crabb, J.W., Polans, A.S. 1993. Identification of the N-terminal region in rhodopsin kinase involved in its interaction with rhodopsin. J. Biol. Chem. 268:6004–6013

  35. Pitcher, J.A., Inglese, J., Higgins, J.B., Arriza, J.L., Casey, P.J., Kim, C., Benovic, J.L., Kwatra, M.M., Caron, M.G., Lefkowitz, R.J. 1992. Roe of βγ subunits in targeting the β-adrenergic receptor kinase to membrane bound receptors. Science 257:1264–1267

  36. Pitcher, J.A., Touhara, K., Payne, S.E., Lefkowitz, R.J. 1995. Pleckstrin homology domain-mediated membrane association and activation of the β-adrenergic receptor kinase requires coordinate interaction with Gβγ subunits and lipid. J. Biol. Chem. 270:11707–11710

  37. Pitcher, J.A., Fredericks, Z.L., Stone, W.C., Premont, R.T., Stoffel, R.H., Koch, W.J., Lefkowitz, R.J. 1996. Phosphatidylinositol 4,5-bisphosphate (PIP2)-enhanced G protein-coupled receptor kinase (GRK) activity: Location, structure and regulation of the PIP2 binding site distinguishes the GRK subfamilies. J. Biol. Chem. 271:24907–24913

  38. Premont, R.T., Inglese, J., Lefkowitz, R.J. 1995. Protein kinases that phosphorylate activated G protein-coupled receptors. FASEB J. 9:175–182

  39. Premont, R.T., Koch, W.J., Inglese, J., Lefkowitz, R.J. 1994. Identification, purification, and characterization of GRK5, a member of the family of G protein-coupled receptor kinases. J. Biol. Chem. 269:6832–6841

  40. Premont, R.T., Macrae, A.D., Stoffel, R.H., Chung, N., Pitcher, J.A., Ambrose, C., Inglese, J., MacDonald, ME., Lefkowitz, R.J. 1996. Characterization of the G protein-coupled receptor kinase GRK4. J. Biol. Chem. 271:6403–6410

  41. Robinson, L.J., Busconi, L., Michel, T. 1995. Agonist-modulated palmitoylation of endothelial nitric oxide synthase. J. Biol. Chem. 270:995–998

  42. Sallese, M., Lombardi, M.S., DeBlasi, A. 1994. Two isoforms of G protein-coupled receptor kinase 4 identified by molecular cloning. Biochem. Biophys. Res. Commun. 199:848–854

  43. Schwinn, D.A., Caron, M.G., Lefkowitz, R.J. 1992. The betaadrenergic receptor as a model for molecular structure-function relationships in G protein-coupled receptors. The Heart and Cardiovascular System, 2nd edition Raven Press, New York

  44. Sterne-Marr, R., Benovic, J.L. 1995. Regulation of G protein-coupled receptors by receptor kinases and arrestins. Vitamins and Hormones 51:193–234

  45. Stoffel, R.H., Randall, R.R., Premont, R.T., Lefkowitz, R.J., Inglese, J. 1994. Palmitoylation of G protein-coupled receptor kinase, GRK6: Lipid modification diversity in the GRK family. J. Biol. Chem. 269:27791–27794

  46. Strasser, R.H., Benovic, J.L., Caron, M.G., Lefkowitz, R.J. 1986. β-agonistand prostaglandin E1-induced translocation of the β-ad-renergic receptor kinase: Evidence that the kinase may act on multiple adenylate cyclase-coupled receptors. Proc. Natl. Acad. Sci. USA 83:6362–6366

  47. Touhara, K., Inglese, J., Pitcher, J.A., Shaw, G., Lefkowitz, R.J. 1994. Binding of G protein βγ-subunits to pleckstrin homology domains. J. Biol. Chem. 269:10217–10220

  48. Touhara, K., Koch, W.J., Hawes, B.E., Lefkowitz, R.J. 1995. Mutational analysis of the pleckstrin homology domain of the betaadrenergic receptor kinase. Differential effects on G beta gamma and phosphatidylinositol 4,5-bisphosphate binding. J. Biol. Chem. 270:17000–17005

  49. Wedegaertner, P.B., Bourne, H.R. 1994. Activation and depalmitoylation of Gs alpha. Cell 77:1063–1070

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Stoffel, R.H., Pitcher, J.A. & Lefkowitz, R.J. Targeting G protein-coupled receptor kinases to their receptor substrates. J. Membrane Biol. 157, 1–8 (1997). https://doi.org/10.1007/s002329900210

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Key words

  • G Protein-Coupled Receptor Kinase
  • βγ
  • Isoprenylation
  • Palmitoylation
  • PIP2