MAPK-dependent Degradation of G Protein-coupled Receptor Kinase 2

Elorza, Ana; Penela, Petronila; Sarnago, Susana; Mayor, Federico

doi:10.1074/jbc.m304314200

Cited by 81 publications

(77 citation statements)

References 40 publications

(54 reference statements)

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“…We have previously shown that phosphorylation of GRK2 at residue S670 by MAPK enhances its proteasomedependent degradation (16). Phosphorylation of GRK2 at S670 was clearly detected throughout the S phase and G2, followed by a sharp decrease at G2/M transition and during mitosis (Fig.…”

Section: Grk2 Levels Are Dynamically Regulated Through the Cell Cyclementioning

confidence: 71%

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G protein–coupled receptor kinase 2 (GRK2) modulation and cell cycle progression

Penela

Rivas

Salcedo

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Cell cycle progression requires changes in the activity or levels of a variety of key signaling proteins. G protein-coupled receptor kinase 2 (GRK2) plays a central role in G protein-coupled receptor regulation. Recent research is uncovering its involvement in additional cellular functions, but the potential role of GRK2 in the cell cycle has not been addressed. We report that GRK2 protein levels are transiently down-regulated during the G2/M transition by a mechanism involving CDK2-mediated phosphorylation of GRK2 at Serine670, which triggers binding to the prolyl-isomerase Pin1 and subsequent degradation. Prevention of GRK2 phosphorylation at S670 impedes normal GRK2 down-regulation and markedly delays cell cycle progression. Interestingly, we find that endogenous GRK2 down-regulation is prevented on activation of the G2/M checkpoint by doxorubicin and that stabilized GRK2 levels in such conditions inversely correlate with the p53 response and the induction of apoptosis, suggesting that GRK2 participates in the regulatory network controlling cell cycle arrest and survival in such conditions. cyclin-dependent kinase 2 | G2/M checkpoint | Pin1 | degradation | p53

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Section: Grk2 Levels Are Dynamically Regulated Through the Cell Cyclementioning

confidence: 71%

“…S7 A-C). Interestingly, this mutant, previously reported to display an intrinsically retarded degradation compared to the wild-type kinase and a deficient S670 phosphorylation-dependent turnover (16,21), also fails to be down-regulated in G2 (Fig. S7D).…”

Section: Grk2 Phosphorylation At Ser670 Is Critical For Grk2 Down-regmentioning

confidence: 77%

G protein–coupled receptor kinase 2 (GRK2) modulation and cell cycle progression

Penela

Rivas

Salcedo

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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“…The pharmacological potential for both positive and negative regulation of RGS proteins to regulate G-protein activity and hence GPCR function has been reviewed recently [54]. GRK2 can be phosphorylated by ERK, resulting in substantially reduced catalytic activity [55] and degradation [56], suggesting another potential site for pharmacological intervention (Table 2).…”

Section: Potential Therapeutic Targets For Selective Grk Inhibitionmentioning

confidence: 99%

Non-visual GRKs: are we seeing the whole picture?

Willets

Challiss

Nahorski

2003

Trends in Pharmacological Sciences

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G-protein-coupled receptor kinases (GRKs) comprise a family of seven mammalian serine/threonine protein kinases that phosphorylate and regulate agonist-occupied or constitutively active G-protein-coupled receptors (GPCRs). Studies of the details and consequences of these mechanisms have focused heavily on the original b-adrenoceptor kinase (b-ARK) family (GRK2 and GRK3) and, in particular, on phosphorylation-dependent recruitment of adaptor proteins such as the b-arrestins. However, recent work has indicated roles for the other, non-visual GRKs (GRK4, GRK5 and GRK6) and has revealed potential phosphorylation-independent regulation of GPCRs by GRK2 and GRK3. In this article, we review this newer information and attempt to put it into context with GRKs as physiological regulators that could be appropriate targets for future pharmacological intervention.G-protein-coupled receptors (GPCRs) constitute a very large family of heptahelical, integral membrane proteins that mediate a wide variety of physiological processes ranging from the transmission of light and odorant signals to the mediation of neurotransmission and hormonal actions [1,2]. GPCRs represent a major target for therapeutic agents, and the continuing identification of orphan GPCRs offers opportunity for future pharmacological and therapeutic development [3].Most GPCRs display a rapid loss of responsiveness in the continuing (or recurring) presence of an agonist or stimulus, and there is now substantial evidence that this process of desensitization, at least in part, is a consequence of ligand-induced phosphorylation of serine and threonine residues located within the C-terminal domain and/or the third intracellular loop of GPCRs. Two families of protein kinases appear to be predominantly involved: the G-protein-coupled receptor kinases (GRKs), which phosphorylate agonist-occupied GPCRs to mediate homologous receptor phosphorylation, and the second messengeractivated kinases, such as cAMP-dependent kinase (PKA) and protein kinase C (PKC), which can phosphorylate both ligand-bound and other inactive GPCRs in a heterologous manner [4,5]. Phosphorylation by GRKs enhances receptor affinity for non-visual b-arrestins 1 and 2 (arrestin2 and arrestin3), which not only sterically suppresses further interaction between the receptor and G proteins, but also initiates clathrin-mediated endocytosis of phosphorylated receptors and can promote the activation of additional signalling pathways by acting as agonist-regulated adaptor scaffolds [6].Other protein kinases have also been implicated in GPCR regulation. For example, evidence has accumulated that casein kinase 1a might bring about agonistmediated phosphorylation of acetylcholine muscarinic M 3 receptors and light-activated rhodopsin [7]. Casein kinase 1a-mediated phosphorylation does not appear to be associated with reduced responsiveness of the M 3 receptor but probably contributes to the activation of extracellular signal-regulated kinases 1 and 2 (ERK1,2) by this receptor [8,9].Although research in this area h...

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“…Phosphorylation of the receptor by GRK2 allows interaction of β-arrestin with receptor and β-arrestin-mediated recruitment of clathrin, thus initiating receptor internalization, as a prelude to deposphorylation and recycling of the receptor. GRK2 activity was shown to be regulated by phosphorylation on serine residues by other kinases such as PKA, PKC ERK1/2 and on tyrosine residue by kinases such as c-Src [16,18,22,27]. Direct phosphorylation of GRK2 on serine 29 located in the calmodulin binding of GRK2 by PKC leads to an increase in GRK2 activity by eliminating the inhibition exerted by the binding of calmodulin, whereas phosphorylation of Raf-kinase inhibitor protein (RKIP) by PKC and subsequent switching of RKIP binding from its known target, Raf-1 to GRK2, leads to inhibition of GRK2 activity [24,31].…”

Section: Nih-pa Author Manuscriptmentioning

confidence: 99%

“…Most studies on receptor regulation have used GRK2 as a prototype kinase that phosphorylates many G protein-coupled receptors [16][17][18]. The activity and localization of GRK2 are regulated by phosphorylation by kinases such as PKA, protein kinase C (PKC), c-Src, and extracellular regulated kinases (ERK1/2) and binding to signaling molecules such as phosphatidylinositol 4,5-bisphosphate, calmodulin, caveolin, and Gβ γ subunits [14,16,[18][19][20][21][22][23][24][25][26][27]. The interaction of Gβ γ with GRK2 assists the kinase to target to the membrane and stimulates its catalytic activity toward the receptor.…”

Section: Introductionmentioning

confidence: 99%

Cross-regulation of VPAC2 receptor internalization by m2 receptors via c-Src-mediated phosphorylation of GRK2

Mahavadi

Huang

Sriwai

et al. 2007

Regulatory Peptides

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The aim of the study was to examine the mechanisms by which ACh, acting via m2 receptors, regulates GRK2-mediated VPAC 2 receptor desensitization in gastric smooth muscle cells. VIP induced VPAC 2 receptor phosphorylation and internalization in freshly dispersed smooth muscle cells. Co-stimulation with acetylcholine (ACh), in the presence of m3 receptor antagonist, 4-DAMP, augmented VPAC 2 receptor phosphorylation and internalization. The m2 receptor antagonist methoctramine or the c-Src inhibitor PP2 blocked the effect of ACh, suggesting that the augmentation was mediated by c-Src, derived from m2 receptor activation. ACh induced activation of c-Src and phosphorylation of GRK2 and the effects of ACh were blocked by methoctramine, PP2, or by uncoupling of m2 receptors from G i3 with pertussis toxin. In conclusion, we identified a novel mechanism of cross-regulation of GRK2-mediated phosphorylation and internalization of G scoupled VPAC 2 receptors by G i -coupled m2 receptors via tyrosine phosphorylation of GRK2 and stimulation of GRK2 activity. KeywordsSmooth muscle; receptor desensitization; vasoactive intestinal peptide; GRK2 phosphorylation Smooth muscle of the gastrointestinal tract exhibits tone on which rhythmic contractions are superimposed. Both, the frequency and amplitude of rhythmic contractions and the muscle tone, are modulated by excitatory and inhibitory neural inputs from the myenteric plexus of the enteric nervous system. Excitatory transmitters consist of acetylcholine (ACh) and tachykinins, and inhibitory transmitters consist of vasoactive intestinal peptide (VIP), pituitary adenylyl cyclase-activating peptide (PACAP), and nitric oxide (NO) [1,2]. About 30% of the myenteric neurons contain VIP, PACAP, and the NO synthase, the enzyme responsible for generation of neural NO. About 40% of the neurons contain ACh and tachykinins. There is no overlap between these groups of nerve fibers and the fibers project into muscle layers. Excitatory neurons mainly release acetylcholine, whereas inhibitory neurons co-release VIP/ PACAP and NO [1,2].On the smooth muscle of the gastrointestinal tract, ACh interacts with two muscarinic receptors to activate distinct signaling pathways [3][4][5]. The more abundant (~80%) m2 receptors are Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Most studies on receptor regulation have used GRK2 as a prototype kinase that phosphorylates many G protein-coupled receptors [16][17][18]. The activity and localization of GRK2 are regulated by phosphorylation by kinases such as PKA, protein kinase C (PKC), c-Src, and extracellular ...

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MAPK-dependent Degradation of G Protein-coupled Receptor Kinase 2

Cited by 81 publications

References 40 publications

G protein–coupled receptor kinase 2 (GRK2) modulation and cell cycle progression

G protein–coupled receptor kinase 2 (GRK2) modulation and cell cycle progression

Non-visual GRKs: are we seeing the whole picture?

Cross-regulation of VPAC2 receptor internalization by m2 receptors via c-Src-mediated phosphorylation of GRK2

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