The G protein-coupled receptor kinase (GRK) interactome: Role of GRKs in GPCR regulation and signaling

Ribas, Catalina; Penela, Petronila; Murga, Cristina; Salcedo, Alicia; García-Hoz, Carlota; Jurado-Pueyo, María; Aymerich, Ivette; Mayor, Federico

doi:10.1016/j.bbamem.2006.09.019

Cited by 365 publications

(317 citation statements)

References 70 publications

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“…Interestingly, in addition to its reported alteration in cardiovascular and inflammatory pathologies (3,10), emerging data indicate changes in GRK2 expression in certain tumors (11). The fact that general but not cardiac-specific GRK2 knockout mice are embryonic lethal (12) further supports the notion that this protein could play a central, general role in key cellular processes as proliferation or migration.…”

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confidence: 70%

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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confidence: 70%

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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“…In vitro studies have also shown the ability of G␣ q to simultaneously bind to both PLC␤ and phosphatidylinositol 3-kinase (43). Our preliminary data indicate that both G␣ q /PKC and G␣ q /MEK5 association are inhibited in the presence of the GRK2 RH domain, 4 which has been reported to interact with G␣ q and block the interaction with its effector PLC␤ (21,44,45). However, the G␣ q sites required for the interactions with both PKC and MEK5 appear to be different from those involved in PLC␤ binding because a G␣ q mutant that is unable to interact with the latter promotes ERK5 activation and readily associates to PKC.…”

Section: Discussionmentioning

confidence: 99%

Gαq Acts as an Adaptor Protein in Protein Kinase Cζ (PKCζ)-mediated ERK5 Activation by G Protein-coupled Receptors (GPCR)

García-Hoz

Sánchez-Fernández

Diaz‐Meco

et al. 2010

Journal of Biological Chemistry

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G q -coupled G protein-coupled receptors (GPCR) mediate the actions of a variety of messengers that are key regulators of different cellular functions. These receptors can regulate a highly interconnected network of biochemical routes that control the activity of several members of the mitogen-activated protein kinase (MAPK) family. The ERK5 MAPK has been shown to be activated by G q -coupled GPCR via unknown mechanisms. We find that the atypical protein kinase C (PKC), previously reported to interact with the ERK5 activator MEK5 and to be involved in epidermal growth factor-mediated ERK5 stimulation, plays a crucial role in the activation of the ERK5 pathway by G q -coupled GPCR. Stimulation of ERK5 by G q -coupled GPCR is abolished upon pharmacological inhibition of PKC as well as in embryonic fibroblasts obtained from PKC-deficient mice. Both PKC and MEK5 associate to G␣ q upon activation of GPCR, thus forming a ternary complex that seems essential for the activation of ERK5. These data put forward a novel function of G␣ q as a scaffold protein involved in the modulation of the ERK5 cascade by GPCR that could be relevant in G q -mediated physiological functions.The activation of the mitogen-activated protein kinase (MAPK) 3 superfamily plays an important role in a wide variety of signaling pathways involved in embryogenesis, cell proliferation, differentiation, migration, apoptosis, and gene expression. The MAPK superfamily includes the well known extracellular signal-regulated kinases 1 and 2 (ERK1/2), c-Jun N-terminal kinase (JNK1-3), and p38 (␣, ␤, ␥, and ␦) families.In addition, ERK3, ERK4, ERK5 (also termed big MAPK1 or BMK1), and ERK7 are other more recently described MAPK family members that display distinct regulatory mechanisms.A plethora of extracellular stimuli have been found to modulate MAPK cascades (1, 2). Although many aspects remain to be detailed, several studies have described the specific mechanisms by which G protein-coupled receptors (GPCR) can activate the main MAPK families (2-4), which can be modulated by different G␣ or ␤␥ subunits, in a stimulus-or context-specific manner (2, 5).The ERK5 MAPK has been reported to be activated by mitogens (EGF, granulocyte-colony-stimulating factor), agonists of GPCR, cytokines (leukemia inhibitory factor, cardiotrophin-1), and stress (6 -8). ERK5 is selectively activated by the upstream kinase MEK5, which in turn is stimulated by MEKK2 and MEKK3, in a process that appears to involve Src tyrosine kinase activation or the scaffolding function of Gab1 or Lck-associated adaptor (LAD) adaptors depending on the stimuli (7, 9). It has also been described that EGF-mediated ERK5 stimulation requires a direct association between PKC and MEK5 (10) through their respective PB1 domains (11), in a process that may involve scaffold proteins such as p62, to which both . However, the mechanisms by which GPCR stimulate ERK5 are largely unknown. It has been reported that ERK5 stimulation can be triggered by GPCR coupled to the G q and G 12/13 families of heterotrime...

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“…GRK3 (or β-adrenergic receptor kinase 2) belongs to a subfamily of kinases called GRKs (26)(27)(28). GRK3 is best known to phosphorylate the agonist-occupied form of β-adrenergic receptors, leading to desensitization of the receptors to their agonists (29,30).…”

Section: Discussionmentioning

confidence: 99%

GRK3 is essential for metastatic cells and promotes prostate tumor progression

Wang

et al. 2014

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

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The biochemical mechanisms that regulate the process of cancer metastasis are still poorly understood. Because kinases, and the signaling pathways they comprise, play key roles in regulation of many cellular processes, we used an unbiased RNAi in vitro screen and a focused cDNA in vivo screen against human kinases to identify those with previously undocumented roles in metastasis. We discovered that G-protein-coupled receptor kinase 3 (GRK3; or β-adrenergic receptor kinase 2) was not only necessary for survival and proliferation of metastatic cells, but also sufficient to promote primary prostate tumor growth and metastasis upon exogenous expression in poorly metastatic cells in mouse xenograft models. Mechanistically, we found that GRK3 stimulated angiogenesis, at least in part through down-regulation of thrombospondin-1 and plasminogen activator inhibitor type 2. Furthermore, GRK3 was found to be overexpressed in human prostate cancers, especially in metastatic tumors. Taken together, these data suggest that GRK3 plays an important role in prostate cancer progression and metastasis.functional screens | essential kinases | ADRBK2 | TSP-1 | PAI-2 M etastasis, and resultant organ failure, is responsible for more than 90% of cancer deaths (1). However, the biochemical and molecular mechanisms that regulate tumor progression to the metastatic phenotype are still poorly understood, especially the control of survival and proliferation of metastatic cells (2, 3). To form metastases, tumor cells need to complete a multistep process, including escape from primary tumor site, intravasation into circulation, and extravasation into secondary sites, where they must be able to survive and proliferate. Cells at these sites then progress from micrometastases to macrometastases through enhancement of angiogenesis and other processes (4, 5). Recent studies have suggested that cell migration and invasion can occur effectively during early phases of primary tumor development (6-8), and survival and proliferation of metastatic cells may be the rate-limiting step for what we often describe as metastasis (2, 3). As such, the ability to initiate angiogenesis at the metastatic site could serve as a distinguishing functional feature between metastatic and nonmetastatic cells.Our previous work has shown the value of comparing functional differences between closely related cell lines through RNAi screens (9-12). In this study, we performed RNAi screens to compare essential kinase profiles between paired highly metastatic and weakly metastatic human cancer cell lines, and identified kinases that are essential preferentially for highly metastatic cells. To prioritize these kinases for further studies, an orthotopic prostate metastasis model was then used to test the corresponding cDNAs in poorly metastatic cells. From these studies, we discovered that G-protein-coupled receptor kinase 3 (GRK3) is not only essential for survival and proliferation of metastatic cells in vitro and in vivo, but also is capable of promoting primary tumor growth ...

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The G protein-coupled receptor kinase (GRK) interactome: Role of GRKs in GPCR regulation and signaling

Cited by 365 publications

References 70 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

Gαq Acts as an Adaptor Protein in Protein Kinase Cζ (PKCζ)-mediated ERK5 Activation by G Protein-coupled Receptors (GPCR)

GRK3 is essential for metastatic cells and promotes prostate tumor progression

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