The molecular acrobatics of arrestin activation

Gurevich, Vsevolod V.; Gurevich, Eugenia V.

doi:10.1016/j.tips.2003.12.008

Cited by 318 publications

(335 citation statements)

References 56 publications

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“…However, upon agonist stimulation of GPCRs and subsequent receptor phosphorylation, arrestin translocates from the cytosol to the membrane fraction, where it can then associate with GPCRs and direct the desensitization of the receptor (10). The treatment of LS-174T and HCA-7 cells with PGE 2 induced the translocation of ␤-arrestin 1 from the cytosol to the membrane fraction (Fig.…”

Section: Resultsmentioning

confidence: 93%

Role of β-arrestin 1 in the metastatic progression of colorectal cancer

Buchanan

Gorden

Matta

et al. 2006

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

247

210

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G protein-coupled receptor ligand-dependent transactivation of growth factor receptors has been implicated in human cancer cell proliferation, migration, and cell survival. For example, prostaglandin E 2 (PGE2)-induced transactivation of the EGF receptor (EGFR) in colorectal carcinoma cells is mediated by means of a c-Src-dependent mechanism and regulates cell proliferation and migration. Recent evidence indicates that ␤-arrestin 1 may act as an important mediator in G protein-coupled receptor-induced activation of c-Src. Whether ␤-arrestin 1 serves a functional role in these events is, however, unknown. We investigated the effects of PGE 2 on colorectal cancer cells expressing WT and mutant ␤-arrestin 1. Here we report that PGE 2 induces the association of a prostaglandin E receptor 4͞␤-arrestin 1͞c-Src signaling complex resulting in the transactivation of the EGFR and downstream Akt (PKB) signaling. The interaction of ␤-arrestin 1 and c-Src is critical for the regulation of colorectal carcinoma cell migration in vitro as well as metastatic spread of disease to the liver in vivo. These results show that the prostaglandin E͞␤-arrestin 1͞c-Src signaling complex is a crucial step in PGE2-mediated transactivation of the EGFR and may play a pivotal role in tumor metastasis. Furthermore, our data implicate a functional role for ␤-arrestin 1 as a mediator of cellular migration and metastasis. metastasis ͉ prostaglandin E2 ͉ c-Src ͉ EGF receptor ͉ prostaglandin E receptor G protein-coupled receptors (GPCRs) comprise the largest known family of plasma membrane receptors and consist of a seven-transmembrane-spanning region f lanked by an extracellular N terminus and an intracellular C terminus. Upon ligand binding, these receptors couple to heterotrimeric G proteins (G␣-and G␤␥-subunits) and catalyze the exchange of GDP for GTP, thus initiating a multitude of signaling events into the cell. These include the classical activation of phosholipases (phosholipases A, C, and D), protein kinases (PKA and PKC), and lipid kinases (phosphatidylinositol 3-kinase) as well as increased intracellular calcium levels. The desensitization of GPCRs occurs through a multistep process. GPCR kinases are recruited to the receptor by liberated ␤␥-subunits and phosphorylate the receptor on the cytoplasmic tail and intracellular loops. This phosphorylation event triggers the association of arrestin, which then traffics the receptors to clathrin-coated pits for endocytosis (1).Prostaglandins (PG) are important bioactive lipids which exert their effects through the activation of specific GPCRs as well as members of the peroxisome proliferator-activated receptor family. For example, PGE 2 is the ligand for four prostaglandin E (EP) receptor isoforms termed EP1, EP2, EP3, and EP4. Stimulation of these receptors elicits different intracellular responses (2). The stimulation of the EP1 receptor induces an increase in intracellular calcium by means of the activation of phospholipase C. EP2 and EP4 receptors couple to G␣s proteins, which generate incre...

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Section: Resultsmentioning

confidence: 93%

Role of β-arrestin 1 in the metastatic progression of colorectal cancer

Buchanan

Gorden

Matta

et al. 2006

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

247

210

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“…Arrestin activity is often contingent upon receptor phosphorylation (reviewed in [35,36]). Therefore, changes in the concentration of GRKs modulate arrestin-mediated signaling.…”

Section: Functional Significance Of Changes In Arrestin and Grk Exprementioning

confidence: 99%

Arrestins and two receptor kinases are upregulated in Parkinson's disease with dementia

Bychkov

Joyce

et al. 2008

Neurobiology of Aging

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Arrestins and G proteins-coupled receptor kinases (GRKs) regulate signaling and trafficking of G protein-coupled receptors. We investigated changes in the expression of arrestins and GRKs in the striatum of patients with Parkinson's disease without (PD) or with dementia (PDD) at post mortem using Western blotting and ribonuclease protection assay. Both PD and PDD groups had similar degree of dopamine depletion in all striatal regions. Arrestin proteins and mRNAs were increased in the PDD group throughout striatum. Protein and mRNA of GRK5, the major subtype in the human striatum, and GRK3 were also upregulated, whereas GRK2 and 6 were mostly unchanged. The PD group had lower concentration of arrestins and GRKs than the PDD group. There was no statistical link between the load of Alzheimer's pathology and the expression of these signaling proteins. Upregulation of arrestins and GRK in PDD may confer resistance to the therapeutic effects of levodopa often observed in these patients. In addition, increased arrestin and GRK concentrations may lead to dementia via perturbation of multiple signaling mechanisms.

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“…Observed binding to inactive phosphorylated (P-Rh) or active unphosphorylated rhodopsin (Rh*) is usually less than 10% of the binding to P-Rh*, whereas its binding to inactive unphosphorylated rhodopsin (Rh) is barely detectable (15). A sequential multisite binding model was proposed to explain arrestin-1 selectivity (16). This model suggests that arrestin-1 elements that recognize rhodopsin-attached phosphates and active rhodopsin conformation serve as sensors.…”

mentioning

confidence: 99%

Conformation of receptor-bound visual arrestin

Kim

Vishnivetskiy²,

Eps

et al. 2012

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

107

174

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Arrestin-1 (visual arrestin) binds to light-activated phosphorylated rhodopsin (P-Rh*) to terminate G-protein signaling. To map conformational changes upon binding to the receptor, pairs of spin labels were introduced in arrestin-1 and double electron-electron resonance was used to monitor interspin distance changes upon P-Rh* binding. The results indicate that the relative position of the N and C domains remains largely unchanged, contrary to expectations of a "clam-shell" model. A loop implicated in P-Rh* binding that connects β-strands V and VI (the "finger loop," residues 67-79) moves toward the expected location of P-Rh* in the complex, but does not assume a fully extended conformation. A striking and unexpected movement of a loop containing residue 139 away from the adjacent finger loop is observed, which appears to facilitate P-Rh* binding. This change is accompanied by smaller movements of distal loops containing residues 157 and 344 at the tips of the N and C domains, which correspond to "plastic" regions of arrestin-1 that have distinct conformations in monomers of the crystal tetramer. Remarkably, the loops containing residues 139, 157, and 344 appear to have high flexibility in both free arrestin-1 and the P-Rh*complex.A rrestin was first discovered in the visual system as a protein that blocks ("arrests") the signaling of the prototypical G protein-coupled receptor (GPCR) rhodopsin (Rh) via specific binding to the phosphorylated activated form P-Rh* (1). Mammals express four arrestin subtypes: Arrestin-1 and -4 are specific for the visual system, whereas arrestin-2 and -3 are ubiquitous (2). [We use systematic names of arrestins: arrestin-1 (historic names S-antigen, 48-kDa protein, or visual or rod arrestin), arrestin-2 (β-arrestin or β-arrestin1), arrestin-3 (β-arrestin2 or hTHY-ARRX), and arrestin-4 (cone or X-arrestin).] The discovery of nonvisual arrestins (3) showed that phosphorylation followed by arrestin binding is a common mechanism of GPCR regulation. Crystal structures of all four arrestin subtypes in their basal state revealed similar topology: two cup-like domains linked by an interdomain hinge ( Fig. 1) (4-7). Arrestin-1 was proposed to undergo a conformational rearrangement during the P-Rh* interaction that results in the release of the C-terminal sequence (C tail) (8, 9) but does not involve major secondary structure changes (8, 10). Recent site-directed spin labeling (SDSL) studies identified specific parts of arrestin-1 engaged by different functional forms of rhodopsin and provided direct evidence of binding-induced conformational changes (11,12). A conformational change in the so-called finger loop (Fig. 1) implicated in P-Rh* recognition was also observed using NMR and fluorescence quenching (13,14). Arrestin-1 shows a remarkable selectivity for P-Rh*. Observed binding to inactive phosphorylated (P-Rh) or active unphosphorylated rhodopsin (Rh*) is usually less than 10% of the binding to P-Rh*, whereas its binding to inactive unphosphorylated rhodopsin (Rh) is barely detectable ...

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The molecular acrobatics of arrestin activation

Cited by 318 publications

References 56 publications

Role of β-arrestin 1 in the metastatic progression of colorectal cancer

Role of β-arrestin 1 in the metastatic progression of colorectal cancer

Arrestins and two receptor kinases are upregulated in Parkinson's disease with dementia

Conformation of receptor-bound visual arrestin

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