Selective engagement of G protein coupled receptor kinases (GRKs) encodes distinct functions of biased ligands

Zidar, David A.; Violin, Jonathan D.; Whalen, Erin J.; Lefkowitz, Robert J.

doi:10.1073/pnas.0904361106

Cited by 244 publications

(282 citation statements)

References 39 publications

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“…Thus, we postulate dimer-induced signaling induces a nonmotile cellular idling response. The differential signaling activated by CXCL12 H25R and CXCL12 2 mirrors prior reports for the CCR7 ligands CCL19 and CCL21, as well as monomeric and dimeric forms of CXCL8 (33,34).…”

Section: Discussionsupporting

confidence: 62%

Monomeric and dimeric CXCL12 inhibit metastasis through distinct CXCR4 interactions and signaling pathways

Drury

Ziarek²,

Gravel

et al. 2011

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

189

236

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Chemokines and chemokine receptors are extensively and broadly involved in cancer metastasis. Previously, we demonstrated that epigenetic silencing of the chemokine CXCL12 sensitizes breast and colon cancer cells to endocrine signaling and metastasis to distant tissues. Yet, the precise mechanism whereby CXCL12 production by tumor cells regulates dissemination remains unclear. Here, we show that administration of CXCL12 extended survival of tumorbearing mice by potently limiting metastasis of colorectal carcinoma or murine melanoma. Because secreted CXCL12 is a mixture of monomeric and dimeric species in equilibrium, oligomeric variants that either promote (monomer) or halt (dimer) chemotaxis were used to dissect the mechanisms interrupting carcinoma metastasis. Monomeric CXCL12 mobilized intracellular calcium, inhibited cAMP signaling, recruited β-arrestin-2, and stimulated filamentous-actin accumulation and cell migration. Dimeric CXCL12 activated G-protein-dependent calcium flux, adenylyl cyclase inhibition, and the rapid activation of ERK1/2, but only weakly, if at all, recruited arrestin, stimulated actin polymerization, or promoted chemotaxis. NMR analyses illustrated that CXCL12 monomers made specific contacts with CXCR4 that were lost following dimerization. Our results establish the potential for inhibiting CXCR4-mediated metastasis by administration of CXCL12. Chemokine-mediated migration and β-arrestin responses did not dictate the antitumor effect of CXCL12. We conclude that cellular migration is tightly regulated by selective CXCR4 signaling evoked by unique interactions with distinct ligand quaternary structures.malignancy | functional selectivity | cellular idling | cancer therapeutics | chemokine oligomer C hemokines are chemoattractant cytokines that bind G-protein-coupled receptors and are mediators for many physiological processes including cell trafficking, angiogenesis, and embryogenesis (1-3). Chemokine receptor signaling is linked with cancer metastasis as well as infiltration of tumor-associated immune cells, neoangiogenesis, and proliferation (4, 5). Chemokines as primary mediators of metastasis were first identified by Muller and colleagues who implicated the chemokine receptor CXCR4 in tumor cell trafficking (6-8). At least 23 different cancers have been shown to express elevated levels of CXCR4, sensitizing these cancers to CXCL12 gradients in distant tissues (9). CXCL12 is constitutively expressed in the bone marrow, lungs, and liver, which are common tissues of metastatic growth. Efforts to block metastatic dissemination have mainly used small molecule antagonists of CXCR4 (10) to limit cancer malignancy (11, 12). However, this avenue has proven difficult to move into the clinic (5, 12), suggesting alternative strategies to interfere with CXCR4-guided metastatic homing (for example, by the use of agonists rather than antagonists) are required. Our previous data indicate that epigenetic silencing of the Cxcl12 promoter enhances metastasis of colonic and mammary carcinoma, implicating...

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Section: Discussionsupporting

confidence: 62%

Monomeric and dimeric CXCL12 inhibit metastasis through distinct CXCR4 interactions and signaling pathways

Drury

Ziarek²,

Gravel

et al. 2011

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

189

236

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“…Other studies have shown that β-arrestins and GRK6 are overexpressed in mouse and monkey models of PD (43,44), and that lentiviral-mediated overexpression of GRK6 in rodent and monkey models of PD reduces LIDs (30). GRK6, which lies upstream of β-arrestins in the GPCR signaling cascade, presumably promotes β-arrestin-dependent signaling (45)(46)(47). Therefore, we reasoned that βarr2 might play a critical role in the mechanism of L-DOPA therapy in PD.…”

Section: Resultsmentioning

confidence: 99%

Targeting β-arrestin2 in the treatment ofl-DOPA–induced dyskinesia in Parkinson’s disease

Urs¹,

Bido

Peterson³

et al. 2015

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

100

105

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Parkinson's disease (PD) is characterized by severe locomotor deficits and is commonly treated with the dopamine (DA) precursor L-3,4-dihydroxyphenylalanine (L-DOPA), but its prolonged use causes dyskinesias referred to as L-DOPA-induced dyskinesias (LIDs). Recent studies in animal models of PD have suggested that dyskinesias are associated with the overactivation of G proteinmediated signaling through DA receptors. β-Arrestins desensitize G protein signaling at DA receptors (D1R and D2R) in addition to activating their own G protein-independent signaling events, which have been shown to mediate locomotion. Therefore, targeting β-arrestins in PD L-DOPA therapy might prove to be a desirable approach. Here we show in a bilateral DA-depletion mouse model of Parkinson's symptoms that genetic deletion of β-arrestin2 significantly limits the beneficial locomotor effects while markedly enhancing the dyskinesia-like effects of acute or chronic L-DOPA treatment. Viral rescue or overexpression of β-arrestin2 in knockout or control mice either reverses or protects against LIDs and its key biochemical markers. In other more conventional animal models of DA neuron loss and PD, such as 6-hydroxydopamine-treated mice or rats and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated nonhuman primates, β-arrestin2 overexpression significantly reduced dyskinesias while maintaining the therapeutic effect of L-DOPA. Considerable efforts are being spent in the pharmaceutical industry to identify therapeutic approaches to block LIDs in patients with PD. Our results point to a potential therapeutic approach, whereby development of either a genetic or pharmacological intervention to enhance β-arrestin2-or limit G protein-dependent D1/D2R signaling could represent a more mechanistically informed strategy.is a major catecholamine neurotransmitter that is released by midbrain DA neurons. DA activates G protein-coupled receptors (GPCRs), which belong to the dopamine D1 (D1R and D5R) or D2 (D2R, D3R, and D4R) class of DA receptors that are known to signal via G protein-dependent mechanisms (1, 2). However, recent studies have shown that in addition to G protein-mediated signaling, many GPCRs, including DA receptors, signal through beta-arrestin 1 and 2 (βarr1 and βarr2)-dependent mechanisms (3, 4). The two isoforms of β-arrestin, β-arrestin1 (βarr1) and β-arrestin2 (βarr2) are widely coexpressed in the brain (5, 6). β-Arrestins were originally appreciated for their ability to desensitize (i.e., turn off) GPCR signaling in a GPCR kinase (GRK)-dependent manner (7,8). Binding of β-arrestin to the GPCR sterically hinders G protein binding and in most instances initiates receptor endocytosis via interactions with adaptor protein complex-2 (AP-2) and clathrin (9-11). It is now appreciated that β-arrestins regulate physiology and behaviors independently of G protein signaling through their ability to scaffold multiple intracellular signaling molecules such as kinases and phosphatases (3,4,12,13). Studies from our laboratory have shown that through ...

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“…CCX-CKR was, however, unable to activate downstream signaling to ERK1/2 and Akt upon stimulation with CCL19, whereas CCL19 activates ERK1/2 in a ␤-arrestin2-dependent manner via CCR7 (38). Importantly, ␤-arrestin can activate numerous other kinases as well as phosphatases in addition to ERK1/2 and Akt (39) and the activation of these additional signal effectors through CCX-CKR remains to be investigated, preferably in physiologically relevant assay systems.…”

Section: Figure 8 Potentiation Of Ccx-ckr-mediated Cre Activation Ismentioning

confidence: 99%

β-Arrestin Recruitment and G Protein Signaling by the Atypical Human Chemokine Decoy Receptor CCX-CKR

Watts

Verkaar

Lee

et al. 2013

Journal of Biological Chemistry

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Background: CCX-CKR is considered to be a chemokine decoy receptor that is unable to signal. Results: Chemokines induce ␤-arrestin recruitment to CCX-CKR and pertussis toxin (PTX)-dependent CRE activity. Conclusion: PTX-sensitive G proteins hinder CCX-CKR coupling to other G proteins and consequently keep receptors silent. Significance: Recruitment of ␤-arrestin to CCX-CKR requests re-evaluation of the signaling capacity of this atypical receptor.

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Selective engagement of G protein coupled receptor kinases (GRKs) encodes distinct functions of biased ligands

Cited by 244 publications

References 39 publications

Monomeric and dimeric CXCL12 inhibit metastasis through distinct CXCR4 interactions and signaling pathways

Monomeric and dimeric CXCL12 inhibit metastasis through distinct CXCR4 interactions and signaling pathways

Targeting β-arrestin2 in the treatment ofl-DOPA–induced dyskinesia in Parkinson’s disease

β-Arrestin Recruitment and G Protein Signaling by the Atypical Human Chemokine Decoy Receptor CCX-CKR

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