β-Arrestin Differentially Regulates the Chemokine Receptor CXCR4-mediated Signaling and Receptor Internalization, and This Implicates Multiple Interaction Sites between β-Arrestin and CXCR4

Cheng, Zhi-jie Jey; Zhao, Jing; Sun, Yue; Hu, Wei; Wu, Yalan; Cen, Bo; Wu, Guo-Xiang; Pei, Gang

doi:10.1074/jbc.275.4.2479

Cited by 191 publications

(229 citation statements)

References 45 publications

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“…␤-Arrestins quench some signals from the activated receptor such as in cAMP-dependent protein kinase pathways, and they mediate other signals such as those involved in the MAPK cascades. It has been reported that ␤-arrestins play a crucial role in ␤ 2 -adrenergic receptormediated ERK activation (39), and our previous work also demonstrates that ␤-arrestin2 can enhance the CXCR4-mediated activation of ERK (21). Our current study further reveals that ␤-arrestin2 is crucially involved in the chemokine-induced activation of p38 MAPK.…”

Section: Discussionsupporting

confidence: 78%

“…Our previous study demonstrates that ␤-arrestin can functionally interact with CXCR4 on SDF-1 stimulation and thus significantly attenuate CXCR4-mediated G-protein activation and promote CXCR4 internalization (21). Recent discoveries indicate that ␤-arrestin also plays an important role as a scaffold that links GPCRs to mitogen-activated protein kinase (MAPK) cascades such as Raf, ERK, ASK1, and c-Jun NH 2 -terminal kinase 3 (22).…”

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confidence: 99%

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β-Arrestin2 Is Critically Involved in CXCR4-mediated Chemotaxis, and This Is Mediated by Its Enhancement of p38 MAPK Activation

Sun¹,

Cheng²,

Ma³

et al. 2002

Journal of Biological Chemistry

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338

295

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Chemotaxis mediated by chemokine receptors such as CXCR4 plays a key role in lymphocyte homing and hematopoiesis as well as in breast cancer metastasis. We have demonstrated previously that ␤-arrestin2 functions to attenuate CXCR4-mediated G protein activation and to enhance CXCR4 internalization. Here we show further that the expression of ␤-arrestin2 in both HeLa and human embryonic kidney 293 cells significantly enhances the chemotactic efficacy of stromal cell-derived factor 1␣, the specific agonist of CXCR4, whereas the suppression of ␤-arrestin2 endogenous expression by antisense or RNA-mediated interference technology considerably attenuates stromal cell-derived factor 1␣-induced cell migration. Expression of ␤-arrestin2 also augmented chemokine receptor CCR5-mediated but not epidermal growth factor receptor-mediated chemotaxis, indicating the specific effect of ␤-arrestin2. Further analysis reveals that expression of ␤-arrestin2 strengthened CXCR4-mediated activation of both p38 MAPK and ERK, and the suppression of ␤-arrestin2 expression blocked the activation of two kinases. Interestingly, inhibition of p38 MAPK activation (but not ERK activation) by its inhibitors or by expression of a dominantnegative mutant of p38 MAPK effectively blocked the chemotactic effect of ␤-arrestin2. Expression of a dominant-negative mutant of ASK1 also exerted the similar blocking effect. The results of our study suggest that ␤-arrestin2 can function not only as a regulator of CXCR4 signaling but also as a mediator of stromal cellderived factor 1␣-induced chemotaxis and that this activity probably occurs via the ASK1/p38 MAPK pathway.

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Section: Discussionsupporting

confidence: 78%

mentioning

confidence: 99%

β-Arrestin2 Is Critically Involved in CXCR4-mediated Chemotaxis, and This Is Mediated by Its Enhancement of p38 MAPK Activation

Sun¹,

Cheng²,

Ma³

et al. 2002

Journal of Biological Chemistry

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338

295

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“…This suggests that receptor phosphorylation is not a critical determinant of ␤-arrestin recruitment to the agonist-occupied CCR5. Alternatively, serine residues in the ICLs may be phosphorylated by GRKs and serve as ␤-arrestin recruitment sites, as has been shown previously for CXCR4 (Cheng et al, 2000). Fourth, substituting the C-tail of CCR5 for the C-tail of CXCR4 transferred the slow trafficking phenotype of CCR5 to the X4-R5 chimera.…”

Section: Discussionmentioning

confidence: 73%

Distinct Mechanisms of Agonist-induced Endocytosis for Human Chemokine Receptors CCR5 and CXCR4

Venkatesan

Rose

Lodge

et al. 2003

MBoC

105

111

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Here we demonstrate that the rate of ligand-induced endocytosis of CCR5 in leukocytes and expression systems is significantly slower than that of CXCR4 and requires prolonged agonist treatment, suggesting that these two receptors use distinct mechanisms. We show that the C-terminal domain of CCR5 is the determinant of its slow endocytosis phenotype. When the C-tail of CXCR4 was exchanged for that of CCR5, the resulting CXCR4-CCR5 (X4-R5) chimera displayed a CCR5-like trafficking phenotype. We found that the palmitoylated cysteine residues in this domain anchor CCR5 to plasma membrane rafts. CXCR4 and a C-terminally truncated CCR5 mutant (CCR5-KRFX) lacking these cysteines are not raft associated and are endocytosed by a clathrin-dependent pathway. Genetic inhibition of clathrin-mediated endocytosis demonstrated that a significant fraction of ligand-occupied CCR5 trafficked by clathrin-independent routes into caveolin-containing vesicular structures. Thus, the palmitoylated C-tail of CCR5 is the major determinant of its raft association and endocytic itineraries, differentiating it from CXCR4 and other chemokine receptors. This novel feature of CCR5 may modulate its signaling potential and could explain its preferential use by HIV for person-to-person transmission of disease. INTRODUCTIONClathrin-mediated endocytosis has been the general paradigm and the most extensively studied mechanism of ligand-induced receptor internalization (Schmid, 1997). However, in recent years, alternative clathrin-independent mechanisms have been described for the uptake of viruses, toxins, and receptors that lack conventional endocytic signals ). Among the latter mechanisms, cholesterol-rich structures called caveolae (Anderson, 1998;Kurzchalia and Parton, 1999) and lipid rafts have been implicated in diverse membrane processes including the assembly of signaling receptor complexes (Simons and Toomre, 2000). Endocytosis of some receptors such as the ␣ subunit of the IL-2 receptor (Tac antigen) and MHC-I, which lack canonical endocytic signals, follow distinct itineraries regulated by the small GTP binding protein, ADP-ribosylation factor 6 (Arf6; Radhakrishna and Donaldson, 1997;Sugita et al., 1999). Clathrin-independent endocytic itineraries are slower than the clathrin-dependent pathway and are functionally relevant in that the long residence time of occupied receptors at the cell surface may enable coupling to multiple signaling pathways.Article published online ahead of print. Mol. Biol. Cell 10.1091/ mbc.E02-11-0714. Article and publication date are available at www.molbiolcell.org/cgi/doi/10.1091/mbc.E02-11-0714. † Corresponding author. E-mail address: aradhana@helix.nih.gov or sv1s@nih.gov. § Present address: INRS-Institut Armand-Frappier, Université du Québec, 531 des Prairies, Laval (Québec), Canada H7V 1B7. Abbreviations used: AOP-RANTES, aminooxypentane-regulated on activation, normal T-cell expressed and secreted; APC, allophycocyanin; Arf6, ADP-ribosylation factor 6; CCV, clathrin-coated vesicles; CHO, Chinese hamster o...

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“…For some receptors, the intracellular loops are important for interaction with arrestins (51-54); for some, it is the C terminus (55)(56)(57)(58)(59)(60), and for others, both the loops and the C terminus may interact with arrestins but with different affinities (61). Our previous results demonstrated that truncation of the C terminus of the human PAFR from cysteine 317 abrogated receptor internalization (39).…”

Section: Discussionmentioning

confidence: 99%

Agonist-induced Internalization of the Platelet-activating Factor Receptor Is Dependent on Arrestins but Independent of G-protein Activation

Chen

Dupré

Gouill

et al. 2002

Journal of Biological Chemistry

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As with most G-protein-coupled receptors, repeated agonist stimulation of the platelet-activating factor receptor (PAFR) results in its desensitization, sequestration, and internalization. In this report, we show that agonist-induced PAFR internalization is independent of G-protein activation but is dependent on arrestins and involves the interaction of arrestins with a limited region of the PAFR C terminus. In cotransfected COS-7 cells, both arrestin-2 and arrestin-3 could be coimmunoprecipitated with PAFR, and agonist stimulation of PAFR induced the translocation of both arrestin-2 and arrestin-3. Furthermore, coexpression of arrestin-2 with PAFR potentiated receptor internalization, whereas agonist-induced PAFR internalization was inhibited by a dominant negative mutant of arrestin-2. The coexpression of a minigene encoding the C-terminal segment of the receptor abolished PAF-induced arrestin translocation and inhibited PAFR internalization. Using C terminus deletion mutants, we determined that the association of arrestin-2 with the receptor was dependent on the region between threonine 305 and valine 330 because arrestin-2 could be immunoprecipitated with the mutant PAFRstop330 but not PAFRstop305. Consistently, stop330 could mediate agonist-induced arrestin-2 translocation, whereas stop305 could not. Two other deletion mutants with slightly longer regions of the C terminus, PAFRstop311 and PAFRstop317, also failed to induce arrestin-2 translocation. Finally, the PAFR mutant Y293A, containing a single substitution in the putative internalization motif DPXXY in the seventh transmembrane domain (which we had shown to be able to internalize but not to couple to G-proteins) could efficiently induce arrestin translocation. Taken together, our results indicate that ligand-induced PAFR internalization is dependent on arrestins, that PAFR can associate with both arrestin-2 and -3, and that their translocation involves interaction with the region of residues 318 -330 in the PAFR C terminus but is independent of G-protein activation.Cell responsiveness to agonists of G-protein-coupled receptors (GPCRs) 1 is usually characterized by a rapid desensitization to subsequent exposures, followed by a resensitization in the absence of stimulation (1-4). The internalization of GPCRs is believed to be responsible, at least in part, for desensitization and/or for resensitization (5-10) of many GPCRs, the prototype being the ␤ 2 -adrenoreceptor (5, 6, 11-14). Members of the arrestin family play an important role in the process of GPCR endocytosis (15-17). After agonist-activation, the receptors are phosphorylated by GPCR-specific kinases (GRKs) and second messenger-dependent kinases (18). For the ␤ 2 -adrenoreceptor and other GPCRs, agonist stimulation leads to arrestin recruitment to the plasma membrane and binding with the phosphorylated receptor. Phosphorylation and arrestins prevent coupling of the receptor to the heterotrimeric G-protein and are believed to be the key elements of a rapid desensitization (19 -21). Arrestins p...

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β-Arrestin Differentially Regulates the Chemokine Receptor CXCR4-mediated Signaling and Receptor Internalization, and This Implicates Multiple Interaction Sites between β-Arrestin and CXCR4

Cited by 191 publications

References 45 publications

β-Arrestin2 Is Critically Involved in CXCR4-mediated Chemotaxis, and This Is Mediated by Its Enhancement of p38 MAPK Activation

β-Arrestin2 Is Critically Involved in CXCR4-mediated Chemotaxis, and This Is Mediated by Its Enhancement of p38 MAPK Activation

Distinct Mechanisms of Agonist-induced Endocytosis for Human Chemokine Receptors CCR5 and CXCR4

Agonist-induced Internalization of the Platelet-activating Factor Receptor Is Dependent on Arrestins but Independent of G-protein Activation

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