Monocyte Chemoattractant Protein-1-Induced CCR2B Receptor Desensitization Mediated by the G Protein-Coupled Receptor Kinase 2
Monocyte chemoattractant protein 1 (MCP-1) is a member of the chemokine cytokine family, whose physiological function is mediated by binding to the CCR2 and CCR4 receptors, which are members of the G protein-coupled receptor family. MCP-1 plays a critical role in both activation and migration of leu...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 1998-03, Vol.95 (6), p.2985-2990 |
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| container_title | Proceedings of the National Academy of Sciences - PNAS |
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| creator | Aragay, A. M. Mellado, M. Frade, J. M. R. Martin, A. M. Jimenez-Sainz, M. C. C. Martinez-A Mayor, F. |
| description | Monocyte chemoattractant protein 1 (MCP-1) is a member of the chemokine cytokine family, whose physiological function is mediated by binding to the CCR2 and CCR4 receptors, which are members of the G protein-coupled receptor family. MCP-1 plays a critical role in both activation and migration of leukocytes. Rapid chemokine receptor desensitization is very likely essential for accurate chemotaxis. In this report, we show that MCP-1 binding to the CCR2 receptor in Mono Mac 1 cells promotes the rapid desensitization of MCP-1-induced calcium flux responses. This desensitization correlates with the Ser/Thr phosphorylation of the receptor and with the transient translocation of the G protein-coupled receptor kinase 2 (GRK2, also called β -adrenergic kinase 1 or β ARK1) to the membrane. We also demonstrate that GRK2 and the uncoupling protein β -arrestin associate with the receptor, forming a macromolecular complex shortly after MCP-1 binding. Calcium flux responses to MCP-1 in HEK293 cells expressing the CCR2B receptor were also markedly reduced upon cotransfection with GRK2 or the homologous kinase GRK3. Nevertheless, expression of the GRK2 dominant-negative mutant β ARK-K220R did not affect the initial calcium response, but favored receptor response to a subsequent challenge by agonists. The modulation of the CCR2B receptor by GRK2 suggests an important role for this kinase in the regulation of monocyte and lymphocyte response to chemokines. |
| doi_str_mv | 10.1073/pnas.95.6.2985 |
| format | Article |
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M. ; Mellado, M. ; Frade, J. M. R. ; Martin, A. M. ; Jimenez-Sainz, M. C. ; C. Martinez-A ; Mayor, F.</creator><creatorcontrib>Aragay, A. M. ; Mellado, M. ; Frade, J. M. R. ; Martin, A. M. ; Jimenez-Sainz, M. C. ; C. Martinez-A ; Mayor, F.</creatorcontrib><description>Monocyte chemoattractant protein 1 (MCP-1) is a member of the chemokine cytokine family, whose physiological function is mediated by binding to the CCR2 and CCR4 receptors, which are members of the G protein-coupled receptor family. MCP-1 plays a critical role in both activation and migration of leukocytes. Rapid chemokine receptor desensitization is very likely essential for accurate chemotaxis. In this report, we show that MCP-1 binding to the CCR2 receptor in Mono Mac 1 cells promotes the rapid desensitization of MCP-1-induced calcium flux responses. This desensitization correlates with the Ser/Thr phosphorylation of the receptor and with the transient translocation of the G protein-coupled receptor kinase 2 (GRK2, also called β -adrenergic kinase 1 or β ARK1) to the membrane. We also demonstrate that GRK2 and the uncoupling protein β -arrestin associate with the receptor, forming a macromolecular complex shortly after MCP-1 binding. Calcium flux responses to MCP-1 in HEK293 cells expressing the CCR2B receptor were also markedly reduced upon cotransfection with GRK2 or the homologous kinase GRK3. Nevertheless, expression of the GRK2 dominant-negative mutant β ARK-K220R did not affect the initial calcium response, but favored receptor response to a subsequent challenge by agonists. The modulation of the CCR2B receptor by GRK2 suggests an important role for this kinase in the regulation of monocyte and lymphocyte response to chemokines.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.95.6.2985</identifier><identifier>PMID: 9501202</identifier><language>eng</language><publisher>United States: National Academy of Sciences of the United States of America</publisher><subject>Antibodies ; Arrestin - metabolism ; beta-Adrenergic Receptor Kinases ; Biological Sciences ; Biological Transport ; Calcium ; Calcium - metabolism ; Cell Compartmentation ; Cell lines ; Cellular biology ; Chemokine CCL2 - pharmacology ; Chemokine receptors ; Chemokines ; Cyclic AMP-Dependent Protein Kinases - genetics ; Cyclic AMP-Dependent Protein Kinases - metabolism ; G-Protein-Coupled Receptor Kinase 3 ; HEK293 cells ; Humans ; Inurement ; Lymphocytes ; Monocytes - drug effects ; Phosphorylation ; Protein Binding ; Protein-Serine-Threonine Kinases - metabolism ; Proteins ; Receptor Protein-Tyrosine Kinases - genetics ; Receptor Protein-Tyrosine Kinases - metabolism ; Receptors ; Receptors, CCR2 ; Receptors, Chemokine ; Receptors, Cytokine - metabolism ; Recombinant Proteins - metabolism</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 1998-03, Vol.95 (6), p.2985-2990</ispartof><rights>Copyright 1993-1998 National Academy of Sciences</rights><rights>Copyright National Academy of Sciences Mar 17, 1998</rights><rights>Copyright © 1998, The National Academy of Sciences 1998</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c579t-2824a913265322b4102e670125c7b4fdb03a789d1e4e7a7456dac54b3467736a3</citedby><cites>FETCH-LOGICAL-c579t-2824a913265322b4102e670125c7b4fdb03a789d1e4e7a7456dac54b3467736a3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://www.pnas.org/content/95/6.cover.gif</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/44784$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/44784$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,723,776,780,799,881,27901,27902,53766,53768,57992,58225</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/9501202$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Aragay, A. M.</creatorcontrib><creatorcontrib>Mellado, M.</creatorcontrib><creatorcontrib>Frade, J. M. R.</creatorcontrib><creatorcontrib>Martin, A. M.</creatorcontrib><creatorcontrib>Jimenez-Sainz, M. C.</creatorcontrib><creatorcontrib>C. Martinez-A</creatorcontrib><creatorcontrib>Mayor, F.</creatorcontrib><title>Monocyte Chemoattractant Protein-1-Induced CCR2B Receptor Desensitization Mediated by the G Protein-Coupled Receptor Kinase 2</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>Monocyte chemoattractant protein 1 (MCP-1) is a member of the chemokine cytokine family, whose physiological function is mediated by binding to the CCR2 and CCR4 receptors, which are members of the G protein-coupled receptor family. MCP-1 plays a critical role in both activation and migration of leukocytes. Rapid chemokine receptor desensitization is very likely essential for accurate chemotaxis. In this report, we show that MCP-1 binding to the CCR2 receptor in Mono Mac 1 cells promotes the rapid desensitization of MCP-1-induced calcium flux responses. This desensitization correlates with the Ser/Thr phosphorylation of the receptor and with the transient translocation of the G protein-coupled receptor kinase 2 (GRK2, also called β -adrenergic kinase 1 or β ARK1) to the membrane. We also demonstrate that GRK2 and the uncoupling protein β -arrestin associate with the receptor, forming a macromolecular complex shortly after MCP-1 binding. Calcium flux responses to MCP-1 in HEK293 cells expressing the CCR2B receptor were also markedly reduced upon cotransfection with GRK2 or the homologous kinase GRK3. Nevertheless, expression of the GRK2 dominant-negative mutant β ARK-K220R did not affect the initial calcium response, but favored receptor response to a subsequent challenge by agonists. 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M.</au><au>Mellado, M.</au><au>Frade, J. M. R.</au><au>Martin, A. M.</au><au>Jimenez-Sainz, M. C.</au><au>C. Martinez-A</au><au>Mayor, F.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Monocyte Chemoattractant Protein-1-Induced CCR2B Receptor Desensitization Mediated by the G Protein-Coupled Receptor Kinase 2</atitle><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle><addtitle>Proc Natl Acad Sci U S A</addtitle><date>1998-03-17</date><risdate>1998</risdate><volume>95</volume><issue>6</issue><spage>2985</spage><epage>2990</epage><pages>2985-2990</pages><issn>0027-8424</issn><eissn>1091-6490</eissn><abstract>Monocyte chemoattractant protein 1 (MCP-1) is a member of the chemokine cytokine family, whose physiological function is mediated by binding to the CCR2 and CCR4 receptors, which are members of the G protein-coupled receptor family. MCP-1 plays a critical role in both activation and migration of leukocytes. Rapid chemokine receptor desensitization is very likely essential for accurate chemotaxis. In this report, we show that MCP-1 binding to the CCR2 receptor in Mono Mac 1 cells promotes the rapid desensitization of MCP-1-induced calcium flux responses. This desensitization correlates with the Ser/Thr phosphorylation of the receptor and with the transient translocation of the G protein-coupled receptor kinase 2 (GRK2, also called β -adrenergic kinase 1 or β ARK1) to the membrane. We also demonstrate that GRK2 and the uncoupling protein β -arrestin associate with the receptor, forming a macromolecular complex shortly after MCP-1 binding. Calcium flux responses to MCP-1 in HEK293 cells expressing the CCR2B receptor were also markedly reduced upon cotransfection with GRK2 or the homologous kinase GRK3. Nevertheless, expression of the GRK2 dominant-negative mutant β ARK-K220R did not affect the initial calcium response, but favored receptor response to a subsequent challenge by agonists. The modulation of the CCR2B receptor by GRK2 suggests an important role for this kinase in the regulation of monocyte and lymphocyte response to chemokines.</abstract><cop>United States</cop><pub>National Academy of Sciences of the United States of America</pub><pmid>9501202</pmid><doi>10.1073/pnas.95.6.2985</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Antibodies Arrestin - metabolism beta-Adrenergic Receptor Kinases Biological Sciences Biological Transport Calcium Calcium - metabolism Cell Compartmentation Cell lines Cellular biology Chemokine CCL2 - pharmacology Chemokine receptors Chemokines Cyclic AMP-Dependent Protein Kinases - genetics Cyclic AMP-Dependent Protein Kinases - metabolism G-Protein-Coupled Receptor Kinase 3 HEK293 cells Humans Inurement Lymphocytes Monocytes - drug effects Phosphorylation Protein Binding Protein-Serine-Threonine Kinases - metabolism Proteins Receptor Protein-Tyrosine Kinases - genetics Receptor Protein-Tyrosine Kinases - metabolism Receptors Receptors, CCR2 Receptors, Chemokine Receptors, Cytokine - metabolism Recombinant Proteins - metabolism |
| title | Monocyte Chemoattractant Protein-1-Induced CCR2B Receptor Desensitization Mediated by the G Protein-Coupled Receptor Kinase 2 |
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