Isoprenylation in regulation of signal transduction by G-protein-coupled receptor kinases

@article{Inglese1992IsoprenylationIR,
  title={Isoprenylation in regulation of signal transduction by G-protein-coupled receptor kinases},
  author={James Inglese and W. Koch and Marc G. Caron and Robert J. Lefkowitz},
  journal={Nature},
  year={1992},
  volume={359},
  pages={147-150}
}
RHODOPSIN kinase1 and β-adrenergic receptor kinase (β ARK)2 are related members of a serine/threonine kinase family that specifically initiate deactivation of G-protein-coupled receptors. After stimulus-mediated receptor activation, these cytoplasmic kinases translocate to the plasma membrane3,4. Here we show that the molecular basis for this event involves a class of unsaturated lipids called isoprenoids. Covalent modification in vivo of rhodopsin kinase by a 15-C (farnesyl) isoprenoid5… 
Lipid-mediated Regulation of G Protein-coupled Receptor Kinases 2 and 3 (*)
TLDR
A novel finding that membrane lipids modulate βARK activity in vitro in a manner that is analogous and competitive with G is reported, submitting the intriguing possibility that both lipids and G proteins co-regulate the function of GRKs.
The Role of Receptor Kinases and Arrestin-Like Proteins in G-Protein-Linked Receptor Desensitization
TLDR
A biochemical mechanism only recently appreciated by which activated G-protein-coupled receptors become desensitized involves two families of proteins: receptor-specific kinases and the arrestin-like proteins.
The β-Adrenergic Receptor Kinase (GRK2) Is Regulated by Phospholipids (*)
TLDR
The direct regulation of GRK2 activity by phospholipids is demonstrated and supports the hypothesis that this effect is the result of a conformational change within the kinase.
Regulation of the G Protein-coupled Receptor Kinase GRK5 by Protein Kinase C*
TLDR
The results suggest that PKC might play an important role in modulating the ability of GRK5 to regulate receptor signaling and that GRK phosphorylation by PKC may serve as a disparate mechanism for regulating GRK activity.
Protein kinases that phosphorylate activated G protein‐coupled receptors
TLDR
All GRKs appear to play the same general cellular role of desensitizing activated G protein‐coupled receptors, but utilize distinctly individual means to the same end, which are just beginning to be defined.
Dual Effect of β-Adrenergic Receptors on Mitogen-activated Protein Kinase
TLDR
MAP kinase activation by isoproterenol was not affected by depletion of protein kinase C, but it was completely abolished by expression of Ras-inhibiting molecules, and signaling from β-adrenergic receptors to MAP kinase involves an activating signal mediated by βγ subunits acting on a Ras-dependent pathway and a Gαs-induced inhibitory signal mediatedby cAMP and PKA.
Mutational Analysis of Gβγ and Phospholipid Interaction with G Protein-coupled Receptor Kinase 2*
TLDR
Several specific GRK2 binding determinants for Gβγ and phospholipids are identified and it is demonstrated that G βγ binding is the limiting step forGRK2-dependent receptor phosphorylation in cells.
G protein-coupled receptor kinases.
TLDR
This review focuses on the regulation of GRK activity by a variety of allosteric and other factors: agonist-stimulated GPCRs, beta gamma subunits of heterotrimeric GTP- binding proteins, phospholipid cofactors, the calcium-binding proteins calmodulin and recoverin, posttranslational isoprenylation and palmitoylation, autophosphorylation, and protein kinase C-mediated GRK phosphorylation.
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References

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TLDR
It is reported here that βARK is also capable of phosphorylating rhodopsin in a totally light-dependent fashion, and rhodopin kinase can phosphorylate the agonist-occupied βAR.
Beta-adrenergic receptor kinase: primary structure delineates a multigene family.
TLDR
Genomic DNA blot analysis suggests that beta-ARK may be the first sequenced member of a multigene family of receptor kinases, and appears to be important in mediating rapid agonist-specific (homologous) desensitization.
The receptor kinase family: primary structure of rhodopsin kinase reveals similarities to the beta-adrenergic receptor kinase.
TLDR
From the common structural features, it is concluded that both RK and beta ARK are members of a newly delineated gene family of guanine nucleotide-binding protein-coupled receptor kinases that may function in diverse pathways to regulate the function of such receptors.
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TLDR
Additional studies characterize this enzyme and suggest that it is responsible for the geranylgeranyl modification of a number of GTP-binding proteins (or their subunits) that contain a consensus prenylation sequence ending in leucine.
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TLDR
The results suggest that the first step in homologous desensitization of the beta-adrenergic receptor may be an agonist-promoted translocation of beta-ar kinase from cytosol to plasma membrane and that beta-AR kinase may represent a more general adenylate cyclase-coupled receptor kinase that participates in regulating the function of many such receptors.
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TLDR
Isoprenylation of gamma subunits by the geranylgeranyl group is presumed to contribute to the association of G proteins with membranes.
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TLDR
It is reported that the processing of ras proteins involves addition of a farnesyl moiety, apparently at the COOH-terminal Cysteine analogous to the cysteine modified in the yeast peptides, and that farNESylation may be important for membrane association and transforming activity of rAS proteins.
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