Regulation of Human Chemokine Receptors CXCR4

Haribabu, Bodduluri; Richardson, Ricardo M.; Fisher, Ian; Sozzani, Silvano; Peiper, Stephen C.; Horuk, Richard; Ali, Hydar; Snyderman, Ralph

doi:10.1074/jbc.272.45.28726

Cited by 261 publications

(107 citation statements)

References 51 publications

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“…Upon receptor activation, these carboxyl-terminal serines and threonines are phosphorylated by G protein-related kinases, which allow ␤-arrestin binding and can lead to both G protein uncoupling and internalization by targeting receptors to clathrin-coated pits (8,41). Wild-type-CXCR3 and Tail(Ϫ)-CXCR3 were immunoprecipitated from extracts made from HEK293 cells transiently transfected with plasmids encoding FLAG-tagged versions of these receptors (Fig.…”

Section: Resultsmentioning

confidence: 99%

Intracellular Domains of CXCR3 That Mediate CXCL9, CXCL10, and CXCL11 Function

Colvin

Campanella

Sun

et al. 2004

Journal of Biological Chemistry

234

215

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The chemokine receptor CXCR3 is a G protein-coupled receptor found predominantly on T cells that is activated by three ligands as follows: CXCL9 (Mig), CXCL10 (IP-10), and CXCL11 (I-TAC). Previously, we have found that of the three ligands, CXCL11 is the most potent inducer of CXCR3 internalization and is the physiologic inducer of CXCR3 internalization after T cell contact with activated endothelial cells. We have therefore hypothesized that these three ligands transduce different signals to CXCR3. In light of this hypothesis, we sought to determine whether regions of CXCR3 are differentially required for CXCL9, CXCL10, and CXCL11 function. Here we identified two distinct domains that contributed to CXCR3 internalization. The carboxyl-terminal domain and ␤-arrestin1 were predominantly required by CXCL9 and CXCL10, and the third intracellular loop was predominantly required by CXCL11. Chemotaxis and calcium mobilization induced by all three CXCR3 ligands were dependent on the CXCR3 carboxyl terminus and the DRY sequence in the third trans-membrane domain. Our findings demonstrate that distinct domains of CXCR3 mediate its functions and suggest that the differential requirement of these domains contributes to the complexity of the chemokine system.

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Section: Resultsmentioning

confidence: 99%

Intracellular Domains of CXCR3 That Mediate CXCL9, CXCL10, and CXCL11 Function

Colvin

Campanella

Sun

et al. 2004

Journal of Biological Chemistry

234

215

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“…Trafficking of both CXCR4 and CCR5 appears to require the serine/threonine-rich C-tail (21,44). GRKs mediate phosphorylation of agonist-activated receptors on serine and threonine residues (74).…”

Section: Discussionmentioning

confidence: 99%

“…Mutagenesis of CXCR4 and Internalization of Mutant Receptors-The C-tail of CXCR4 has been shown to be required for agonist and PMA-mediated CXCR4 internalization (44). A recent study using mink lung epithelial cells (Mv-1-Lu) showed that Ser-324 and Ser-325 and the dileucine motif at amino acids 328 and 329 appear to be involved in phorbol ester-but not SDF-1␣-mediated CXCR4 internalization (53).…”

Section: Fig 2 Pma-and Rantes-mediated Ccr5 Internalizationmentioning

confidence: 99%

“…The determinants for receptor phosphorylation and internalization of both CCR5 and CXCR4 appear to reside in the Cterminal tail (21,44). The involvement of GRKs and arrestins in CCR5 internalization and desensitization has been reported (21), and residues in the CCR5 C-tail that are phosphorylated in response to different CCR5 agonists have recently been identified (45).…”

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confidence: 99%

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Trafficking of the HIV Coreceptor CXCR4

Orsini¹,

Parent²,

Mundell

et al. 1999

Journal of Biological Chemistry

221

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The G protein-coupled chemokine receptor CXCR4 serves as the primary coreceptor for entry of T-cell tropic human immunodeficiency virus. CXCR4 undergoes tonic internalization as well as internalization in response to stimulation with phorbol esters and ligand (SDF-1␣). We investigated the trafficking of this receptor, and we attempted to define the residues of CXCR4 that were critical for receptor internalization. In both COS-1 and HEK-293 cells transiently overexpressing CXCR4, SDF-1␣ and phorbol esters (PMA) promoted rapid internalization of cell surface receptors as assessed by both enzyme-linked immunosorbent assay and immunofluorescence analysis. Expression of GRK2 and/or arrestins promoted modest additional CXCR4 internalization in response to both PMA and SDF. Both PMA-and SDF-mediated CXCR4 internalization was inhibited by coexpression of dominant negative mutants of dynamin-1 and arrestin-3. Arrestin was also recruited to the plasma membrane and appeared to colocalize with internalized receptors in response to SDF but not PMA. We then evaluated the ability of CXCR4 receptors containing mutations of serines and threonines, as well as a dileucine motif, within the C-terminal tail to be internalized and phosphorylated in response to either PMA or SDF-1␣. This analysis showed that multiple residues within the CXCR4 C-terminal tail appear to mediate both PMA-and SDF-1␣-mediated receptor internalization. The ability of coexpressed GRK2 and arrestins to promote internalization of the CXCR4 mutants revealed distinct differences between respective mutants and suggested that the integrity of the dileucine motif (Ile-328 and Leu-329) and serines 324, 325, 338, and 339 are critical for receptor internalization.

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“…Splenocytes from genetically deficient mice and littermate controls were isolated, pooled, and frozen at Ϫ80°C until use. Membranes were prepared and assayed for GTPase activity (10 g of membrane preparations͞assay) as described (18,19) in the presence and absence of murine CXCL12 (1 M).…”

Section: Methodsmentioning

confidence: 99%

Defective lymphocyte chemotaxis in β-arrestin2- and GRK6-deficient mice

Fong

Premont

Richardson

et al. 2002

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

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278

233

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Lymphocyte chemotaxis is a complex process by which cells move within tissues and across barriers such as vascular endothelium and is usually stimulated by chemokines such as stromal cell-derived factor-1 (CXCL12) acting via G protein-coupled receptors. Because members of this receptor family are regulated (''desensitized'') by G protein-coupled receptor kinase (GRK)-mediated receptor phosphorylation and ␤-arrestin binding, we examined signaling and chemotactic responses in splenocytes derived from knockout mice deficient in various ␤-arrestins and GRKs, with the expectation that these responses might be enhanced. Knockouts of ␤-arrestin2, GRK5, and GRK6 were examined because all three proteins are expressed at high levels in purified mouse CD3؉ T and B220؉ B splenocytes. CXCL12 stimulation of membrane GTPase activity was unaffected in splenocytes derived from GRK5-deficient mice but was increased in splenocytes from the ␤-arrestin2-and GRK6-deficient animals. Surprisingly, however, both T and B cells from ␤-arrestin2-deficient animals and T cells from GRK6-deficient animals were strikingly impaired in their ability to respond to CXCL12 both in transwell migration assays and in transendothelial migration assays. Chemotactic responses of lymphocytes from GRK5-deficient mice were unaffected. Thus, these results indicate that ␤-arrestin2 and GRK6 actually play positive regulatory roles in mediating the chemotactic responses of T and B lymphocytes to CXCL12.L eukocytes migrate to sites of inflammation by recognizing a gradient of chemoattractants, and moving toward the chemoattractant source. This process of ligand recognition, cell polarization and directed cell migration is complex, given that a cell needs to integrate numerous signals arising from different spatial orientations to decide in which direction to move. In lymphocytes, the signals that guide the cell in making these decisions arise from chemokine activation of heptahelical G protein-coupled receptors (GPCR) linked to G␣i proteins. Directional migration, however, requires the activity of G␤␥, but not G␣, proteins (1, 2). In addition, Rho family guanosine triphosphatases (GTPases), the phosphoinositide 3-kinases, and possibly extracellular receptor kinases each play important roles in generating the cell polarity and cytoskeletal reorganization required for directional migration (3-7).Migration to chemokine gradients is dose dependent. Chemotaxis occurs at relatively low concentrations of chemokines, but at higher chemokine concentrations, cells become paralyzed and no longer migrate toward the chemoattractant source. The mechanisms by which cells are paralyzed at high chemokine concentrations are not clear but may involve agonist-dependent desensitization and receptor endocytosis mediated by G proteincoupled receptor kinases (GRKs) and arrestins. GRKs phosphorylate serine and threonine residues in the C terminus and intracellular loops of GPCRs, allowing for the association of arrestins that act to prevent heterotrimeric G␣␤␥ protein association with a...

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Regulation of Human Chemokine Receptors CXCR4

Cited by 261 publications

References 51 publications

Intracellular Domains of CXCR3 That Mediate CXCL9, CXCL10, and CXCL11 Function

Intracellular Domains of CXCR3 That Mediate CXCL9, CXCL10, and CXCL11 Function

Trafficking of the HIV Coreceptor CXCR4

Defective lymphocyte chemotaxis in β-arrestin2- and GRK6-deficient mice

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