The complex G protein‐coupled receptor kinase 2 (GRK2) interactome unveils new physiopathological targets

Penela, Petronila; Murga, Cristina; Ribas, Catalina; Lafarga, Vanesa; Mayor, Federico

doi:10.1111/j.1476-5381.2010.00727.x

Cited by 188 publications

(226 citation statements)

References 80 publications

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“…Coincidently, we show that the impairment of the GRK2/G␣q interaction with a specific association-deficient G␣q mutant (Y261F) greatly enhances G␣q interaction with PKC and its presence in ERK5 complexes, thus promoting ERK5 activation. These findings strengthen the role of PKC as a novel G␣q effector and suggest that G␣q signaling toward the PKC/ERK5 pathway could be effectively modified in pathophysiological contexts where GRK2 expression and/or functionality is altered (36).…”

Section: Discussionsupporting

confidence: 48%

Protein Kinase C ζ Interacts with a Novel Binding Region of Gαq to Act as a Functional Effector

Sánchez-Fernández

Cabezudo

Hernandez-Caballero

et al. 2016

Journal of Biological Chemistry

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Heterotrimeric G proteins play an essential role in the initiation of G protein-coupled receptor (GPCR) signaling through specific interactions with a variety of cellular effectors. We have recently reported that GPCR activation promotes a direct interaction between G␣q and protein kinase C (PKC), leading to the stimulation of the ERK5 pathway independent of the canonical effector PLC␤. We report herein that the activation-dependent G␣q/PKC complex involves the basic PB1-type II domain of PKC and a novel interaction module in G␣q different from the classical effector-binding site. Point mutations in this G␣q region completely abrogate ERK5 phosphorylation, indicating that G␣q/PKC association is required for the activation of the pathway. Indeed, PKC was demonstrated to directly bind ERK5 thus acting as a scaffold between G␣q and ERK5 upon GPCR activation. The inhibition of these protein complexes by G proteincoupled receptor kinase 2, a known G␣q modulator, led to a complete abrogation of ERK5 stimulation. Finally, we reveal that G␣q/ PKC complexes link G␣q to apoptotic cell death pathways. Our data suggest that the interaction between this novel region in G␣q and the effector PKC is a key event in G␣q signaling.

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Section: Discussionsupporting

confidence: 48%

Protein Kinase C ζ Interacts with a Novel Binding Region of Gαq to Act as a Functional Effector

Sánchez-Fernández

Cabezudo

Hernandez-Caballero

et al. 2016

Journal of Biological Chemistry

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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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“…GPCR activation is known to promote the formation of complexes between Gβγ subunits and GRK kinases (20,21). We hypothesized that the antiallodynic response observed with low doses of DMI in Rgs9KO mice is associated with increased levels of GRK2/Gβ complexes, and we used co-IP assays to monitor these complexes in ventral striatal tissue.…”

Section: Resultsmentioning

confidence: 99%

RGS9-2–controlled adaptations in the striatum determine the onset of action and efficacy of antidepressants in neuropathic pain states

Mitsi

Terzi

Purushothaman

et al. 2015

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

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The striatal protein Regulator of G-protein signaling 9-2 (RGS9-2) plays a key modulatory role in opioid, monoamine, and other G-protein-coupled receptor responses. Here, we use the murine spared-nerve injury model of neuropathic pain to investigate the mechanism by which RGS9-2 in the nucleus accumbens (NAc), a brain region involved in mood, reward, and motivation, modulates the actions of tricyclic antidepressants (TCAs). Prevention of RGS9-2 action in the NAc increases the efficacy of the TCA desipramine and dramatically accelerates its onset of action. By controlling the activation of effector molecules by G protein α and βγ subunits, RGS9-2 affects several protein interactions, phosphoprotein levels, and the function of the epigenetic modifier histone deacetylase 5, which are important for TCA responsiveness. Furthermore, information from RNA-sequencing analysis reveals that RGS9-2 in the NAc affects the expression of many genes known to be involved in nociception, analgesia, and antidepressant drug actions. Our findings provide novel information on NAc-specific cellular mechanisms that mediate the actions of TCAs in neuropathic pain states.desipramine | duloxetine | HDAC5 | spared nerve injury | gene expression R egulator of G-protein signaling 9-2 (RGS9-2) is an intracellular modulator of G-protein-coupled receptor (GPCR) function, which is expressed in medium spiny neurons and cholinergic interneurons of the striatum (1, 2). RGS9-2 influences the magnitude and time course of GPCR signaling by promoting GTPase activity of the Gα subunit and by preventing activation of Gα effectors (3). This modulation can also influence the duration of interactions between the Gβγ subunits and their effector molecules. In addition to Gα subunits, RGS9-2 interacts with several scaffolds and signal transduction proteins that affect its function, expression, and cellular localization. Interactions with the Gβ5 subunit and the adaptor protein R7BP determine the stability and cellular localization of RGS9-2, respectively (3, 4). Several recent studies have provided information on the regulation and function of RGS9-2 complexes in the striatum and how these complexes affect pharmacologic responses (2, 5, 6). In particular, RGS9-2 has been shown to modulate the actions of various psychotropic, antiparkinsonian, neuroleptic, and opiate analgesic drugs (1, 7). The nucleus accumbens (NAc) is a striatal brain region that is a major site of antidepressant drug action (8). Recent studies provided information on signal transduction events triggered by tricyclic antidepressants (TCAs) in NAc neurons and identified several second messengers, transcription factors, and epigenetic molecules involved in their therapeutic actions (9-11). TCAs, such as desipramine (DMI) and nortriptyline (NTL), and selective serotonin/norepinephrine reuptake inhibitors (SNRIs) have also been used to treat neuropathic pain, a complex chronic disorder that is highly comorbid with anxiety and depression (12, 13) and is characterized by thermal hyperalgesia, mech...

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The complex G protein‐coupled receptor kinase 2 (GRK2) interactome unveils new physiopathological targets

Cited by 188 publications

References 80 publications

Protein Kinase C ζ Interacts with a Novel Binding Region of Gαq to Act as a Functional Effector

Protein Kinase C ζ Interacts with a Novel Binding Region of Gαq to Act as a Functional Effector

GRK3 is essential for metastatic cells and promotes prostate tumor progression

RGS9-2–controlled adaptations in the striatum determine the onset of action and efficacy of antidepressants in neuropathic pain states

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