Differential Regulation of CXCR4-mediated T-cell Chemotaxis and Mitogen-activated Protein Kinase Activation by the Membrane Tyrosine Phosphatase, CD45
The chemokine receptor CXCR4 and its cognate ligand, stromal cell-derived factor-1α (CXCL12), regulate lymphocyte trafficking and play an important role in host immune surveillance. However, the molecular mechanisms involved in CXCL12-induced and CXCR4-mediated chemotaxis of T-lymphocytes are not c...
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| Veröffentlicht in: | The Journal of biological chemistry 2003-03, Vol.278 (11), p.9536-9543 |
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| creator | Fernandis, Aaron Z Cherla, Rama P Ganju, Ramesh K |
| description | The chemokine receptor CXCR4 and its cognate ligand, stromal cell-derived factor-1α (CXCL12), regulate lymphocyte trafficking
and play an important role in host immune surveillance. However, the molecular mechanisms involved in CXCL12-induced and CXCR4-mediated
chemotaxis of T-lymphocytes are not completely elucidated. In the present study, we examined the role of the membrane tyrosine
phosphatase CD45, which regulates antigen receptor signaling in CXCR4-mediated chemotaxis and mitogen-activated protein kinase
(MAPK) activation in T-cells. We observed a significant reduction in CXCL12-induced chemotaxis in the CD45-negative Jurkat
cell line (J45.01) as compared with the CD45-positive control (JE6.1) cells. Expression of a chimeric protein containing the
intracellular phosphatase domain of CD45 was able to partially restore CXCL12-induced chemotaxis in the J45.01 cells. However,
reconstitution of CD45 into the J45.01 cells restored the CXCL12-induced chemotaxis to about 90%. CD45 had no significant
effect on CXCL12 or human immunodeficiency virus gp120-induced internalization of the CXCR4 receptor. Furthermore, J45.01
cells showed a slight enhancement in CXCL12-induced MAP kinase activity as compared with the JE6.1 cells. We also observed
that CXCL12 treatment enhanced the tyrosine phosphorylation of CD45 and induced its association with the CXCR4 receptor. Pretreatment
of T-cells with the lipid raft inhibitor, methyl-β-cyclodextrin, blocked the association between CXCR4 and CD45 and markedly
abolished CXCL12-induced chemotaxis. Comparisons of signaling pathways induced by CXCL12 in JE6.1 and J45.01 cells revealed
that CD45 might moderately regulate the tyrosine phosphorylation of the focal adhesion components the related adhesion focal
tyrosine kinase/Pyk2, focal adhesion kinase, p130Cas, and paxillin. CD45 has also been shown to regulate CXCR4-mediated activation
and phosphorylation of T-cell receptor downstream effectors Lck, ZAP-70, and SLP-76. Our results show that CD45 differentially
regulates CXCR4-mediated chemotactic activity and MAPK activation by modulating the activities of focal adhesion components
and the downstream effectors of the T-cell receptor. |
| doi_str_mv | 10.1074/jbc.M211803200 |
| format | Article |
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and play an important role in host immune surveillance. However, the molecular mechanisms involved in CXCL12-induced and CXCR4-mediated
chemotaxis of T-lymphocytes are not completely elucidated. In the present study, we examined the role of the membrane tyrosine
phosphatase CD45, which regulates antigen receptor signaling in CXCR4-mediated chemotaxis and mitogen-activated protein kinase
(MAPK) activation in T-cells. We observed a significant reduction in CXCL12-induced chemotaxis in the CD45-negative Jurkat
cell line (J45.01) as compared with the CD45-positive control (JE6.1) cells. Expression of a chimeric protein containing the
intracellular phosphatase domain of CD45 was able to partially restore CXCL12-induced chemotaxis in the J45.01 cells. However,
reconstitution of CD45 into the J45.01 cells restored the CXCL12-induced chemotaxis to about 90%. CD45 had no significant
effect on CXCL12 or human immunodeficiency virus gp120-induced internalization of the CXCR4 receptor. Furthermore, J45.01
cells showed a slight enhancement in CXCL12-induced MAP kinase activity as compared with the JE6.1 cells. We also observed
that CXCL12 treatment enhanced the tyrosine phosphorylation of CD45 and induced its association with the CXCR4 receptor. Pretreatment
of T-cells with the lipid raft inhibitor, methyl-β-cyclodextrin, blocked the association between CXCR4 and CD45 and markedly
abolished CXCL12-induced chemotaxis. Comparisons of signaling pathways induced by CXCL12 in JE6.1 and J45.01 cells revealed
that CD45 might moderately regulate the tyrosine phosphorylation of the focal adhesion components the related adhesion focal
tyrosine kinase/Pyk2, focal adhesion kinase, p130Cas, and paxillin. CD45 has also been shown to regulate CXCR4-mediated activation
and phosphorylation of T-cell receptor downstream effectors Lck, ZAP-70, and SLP-76. Our results show that CD45 differentially
regulates CXCR4-mediated chemotactic activity and MAPK activation by modulating the activities of focal adhesion components
and the downstream effectors of the T-cell receptor.</description><identifier>ISSN: 0021-9258</identifier><identifier>EISSN: 1083-351X</identifier><identifier>DOI: 10.1074/jbc.M211803200</identifier><identifier>PMID: 12519755</identifier><language>eng</language><publisher>United States: American Society for Biochemistry and Molecular Biology</publisher><subject>Adaptor Proteins, Signal Transducing ; Blotting, Western ; Cell Line ; Chemokine CXCL12 ; Chemokines, CXC - metabolism ; Chemotaxis ; Dose-Response Relationship, Drug ; Enzyme Activation ; Flow Cytometry ; Gene Expression Regulation ; Humans ; Jurkat Cells ; Leukocyte Common Antigens - metabolism ; Lymphocyte Specific Protein Tyrosine Kinase p56(lck) - metabolism ; Lymphocytes - metabolism ; MAP Kinase Signaling System ; Microscopy, Confocal ; Microscopy, Fluorescence ; Phosphoproteins - metabolism ; Phosphorylation ; Precipitin Tests ; Protein Structure, Tertiary ; Protein-Tyrosine Kinases - metabolism ; Receptors, Antigen, T-Cell - metabolism ; Receptors, CXCR4 - metabolism ; Signal Transduction ; T-Lymphocytes - metabolism ; Time Factors ; Tyrosine - metabolism ; ZAP-70 Protein-Tyrosine Kinase</subject><ispartof>The Journal of biological chemistry, 2003-03, Vol.278 (11), p.9536-9543</ispartof><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c390t-5a134f72d95c2d441eaf105d64a109f781a2209f6308a603022fa47edbe0ef8e3</citedby><cites>FETCH-LOGICAL-c390t-5a134f72d95c2d441eaf105d64a109f781a2209f6308a603022fa47edbe0ef8e3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/12519755$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Fernandis, Aaron Z</creatorcontrib><creatorcontrib>Cherla, Rama P</creatorcontrib><creatorcontrib>Ganju, Ramesh K</creatorcontrib><title>Differential Regulation of CXCR4-mediated T-cell Chemotaxis and Mitogen-activated Protein Kinase Activation by the Membrane Tyrosine Phosphatase, CD45</title><title>The Journal of biological chemistry</title><addtitle>J Biol Chem</addtitle><description>The chemokine receptor CXCR4 and its cognate ligand, stromal cell-derived factor-1α (CXCL12), regulate lymphocyte trafficking
and play an important role in host immune surveillance. However, the molecular mechanisms involved in CXCL12-induced and CXCR4-mediated
chemotaxis of T-lymphocytes are not completely elucidated. In the present study, we examined the role of the membrane tyrosine
phosphatase CD45, which regulates antigen receptor signaling in CXCR4-mediated chemotaxis and mitogen-activated protein kinase
(MAPK) activation in T-cells. We observed a significant reduction in CXCL12-induced chemotaxis in the CD45-negative Jurkat
cell line (J45.01) as compared with the CD45-positive control (JE6.1) cells. Expression of a chimeric protein containing the
intracellular phosphatase domain of CD45 was able to partially restore CXCL12-induced chemotaxis in the J45.01 cells. However,
reconstitution of CD45 into the J45.01 cells restored the CXCL12-induced chemotaxis to about 90%. CD45 had no significant
effect on CXCL12 or human immunodeficiency virus gp120-induced internalization of the CXCR4 receptor. Furthermore, J45.01
cells showed a slight enhancement in CXCL12-induced MAP kinase activity as compared with the JE6.1 cells. We also observed
that CXCL12 treatment enhanced the tyrosine phosphorylation of CD45 and induced its association with the CXCR4 receptor. Pretreatment
of T-cells with the lipid raft inhibitor, methyl-β-cyclodextrin, blocked the association between CXCR4 and CD45 and markedly
abolished CXCL12-induced chemotaxis. Comparisons of signaling pathways induced by CXCL12 in JE6.1 and J45.01 cells revealed
that CD45 might moderately regulate the tyrosine phosphorylation of the focal adhesion components the related adhesion focal
tyrosine kinase/Pyk2, focal adhesion kinase, p130Cas, and paxillin. CD45 has also been shown to regulate CXCR4-mediated activation
and phosphorylation of T-cell receptor downstream effectors Lck, ZAP-70, and SLP-76. Our results show that CD45 differentially
regulates CXCR4-mediated chemotactic activity and MAPK activation by modulating the activities of focal adhesion components
and the downstream effectors of the T-cell receptor.</description><subject>Adaptor Proteins, Signal Transducing</subject><subject>Blotting, Western</subject><subject>Cell Line</subject><subject>Chemokine CXCL12</subject><subject>Chemokines, CXC - metabolism</subject><subject>Chemotaxis</subject><subject>Dose-Response Relationship, Drug</subject><subject>Enzyme Activation</subject><subject>Flow Cytometry</subject><subject>Gene Expression Regulation</subject><subject>Humans</subject><subject>Jurkat Cells</subject><subject>Leukocyte Common Antigens - metabolism</subject><subject>Lymphocyte Specific Protein Tyrosine Kinase p56(lck) - metabolism</subject><subject>Lymphocytes - metabolism</subject><subject>MAP Kinase Signaling System</subject><subject>Microscopy, Confocal</subject><subject>Microscopy, Fluorescence</subject><subject>Phosphoproteins - metabolism</subject><subject>Phosphorylation</subject><subject>Precipitin Tests</subject><subject>Protein Structure, Tertiary</subject><subject>Protein-Tyrosine Kinases - metabolism</subject><subject>Receptors, Antigen, T-Cell - metabolism</subject><subject>Receptors, CXCR4 - metabolism</subject><subject>Signal Transduction</subject><subject>T-Lymphocytes - metabolism</subject><subject>Time Factors</subject><subject>Tyrosine - metabolism</subject><subject>ZAP-70 Protein-Tyrosine Kinase</subject><issn>0021-9258</issn><issn>1083-351X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2003</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpFkU2P0zAQhi0EYsvClSOyhMSJFI8_muS4yvIltmK1KtLeLCcZN14lcbFdoH-E34tLK60vM9I8fjXzvoS8BrYEVsoPD223XHOAignO2BOyAFaJQii4f0oWjHEoaq6qC_IixgeWn6zhObkArqAulVqQv9fOWgw4J2dGeofb_WiS8zP1ljb3zZ0sJuydSdjTTdHhONJmwMkn88dFauaerl3yW5wL0yX36z93G3xCN9NvbjYR6dVpcNRsDzQNSNc4tcHMSDeH4KPLze3g424wKfPvaXMt1UvyzJox4qtzvSQ_Pn3cNF-Km--fvzZXN0UnapYKZUBIW_K-Vh3vpQQ0FpjqV9IAq21ZgeE8NyvBKrNignFujSyxb5GhrVBckncn3V3wP_cYk55cPJ6Z1_P7qKEqmapBZnB5Aru8cgxo9S64yYSDBqaPSeichH5MIn94c1bet9nCR_xsfQbenoDBbYffLqBune-yuZqXlQbQtRIr8Q9so5Da</recordid><startdate>20030314</startdate><enddate>20030314</enddate><creator>Fernandis, Aaron Z</creator><creator>Cherla, Rama P</creator><creator>Ganju, Ramesh K</creator><general>American Society for Biochemistry and Molecular Biology</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QR</scope><scope>7T5</scope><scope>8FD</scope><scope>FR3</scope><scope>H94</scope><scope>P64</scope></search><sort><creationdate>20030314</creationdate><title>Differential Regulation of CXCR4-mediated T-cell Chemotaxis and Mitogen-activated Protein Kinase Activation by the Membrane Tyrosine Phosphatase, CD45</title><author>Fernandis, Aaron Z ; Cherla, Rama P ; Ganju, Ramesh K</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c390t-5a134f72d95c2d441eaf105d64a109f781a2209f6308a603022fa47edbe0ef8e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2003</creationdate><topic>Adaptor Proteins, Signal Transducing</topic><topic>Blotting, Western</topic><topic>Cell Line</topic><topic>Chemokine CXCL12</topic><topic>Chemokines, CXC - metabolism</topic><topic>Chemotaxis</topic><topic>Dose-Response Relationship, Drug</topic><topic>Enzyme Activation</topic><topic>Flow Cytometry</topic><topic>Gene Expression Regulation</topic><topic>Humans</topic><topic>Jurkat Cells</topic><topic>Leukocyte Common Antigens - metabolism</topic><topic>Lymphocyte Specific Protein Tyrosine Kinase p56(lck) - metabolism</topic><topic>Lymphocytes - metabolism</topic><topic>MAP Kinase Signaling System</topic><topic>Microscopy, Confocal</topic><topic>Microscopy, Fluorescence</topic><topic>Phosphoproteins - metabolism</topic><topic>Phosphorylation</topic><topic>Precipitin Tests</topic><topic>Protein Structure, Tertiary</topic><topic>Protein-Tyrosine Kinases - metabolism</topic><topic>Receptors, Antigen, T-Cell - metabolism</topic><topic>Receptors, CXCR4 - metabolism</topic><topic>Signal Transduction</topic><topic>T-Lymphocytes - metabolism</topic><topic>Time Factors</topic><topic>Tyrosine - metabolism</topic><topic>ZAP-70 Protein-Tyrosine Kinase</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Fernandis, Aaron Z</creatorcontrib><creatorcontrib>Cherla, Rama P</creatorcontrib><creatorcontrib>Ganju, Ramesh K</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Chemoreception Abstracts</collection><collection>Immunology Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Biotechnology and BioEngineering Abstracts</collection><jtitle>The Journal of biological chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Fernandis, Aaron Z</au><au>Cherla, Rama P</au><au>Ganju, Ramesh K</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Differential Regulation of CXCR4-mediated T-cell Chemotaxis and Mitogen-activated Protein Kinase Activation by the Membrane Tyrosine Phosphatase, CD45</atitle><jtitle>The Journal of biological chemistry</jtitle><addtitle>J Biol Chem</addtitle><date>2003-03-14</date><risdate>2003</risdate><volume>278</volume><issue>11</issue><spage>9536</spage><epage>9543</epage><pages>9536-9543</pages><issn>0021-9258</issn><eissn>1083-351X</eissn><abstract>The chemokine receptor CXCR4 and its cognate ligand, stromal cell-derived factor-1α (CXCL12), regulate lymphocyte trafficking
and play an important role in host immune surveillance. However, the molecular mechanisms involved in CXCL12-induced and CXCR4-mediated
chemotaxis of T-lymphocytes are not completely elucidated. In the present study, we examined the role of the membrane tyrosine
phosphatase CD45, which regulates antigen receptor signaling in CXCR4-mediated chemotaxis and mitogen-activated protein kinase
(MAPK) activation in T-cells. We observed a significant reduction in CXCL12-induced chemotaxis in the CD45-negative Jurkat
cell line (J45.01) as compared with the CD45-positive control (JE6.1) cells. Expression of a chimeric protein containing the
intracellular phosphatase domain of CD45 was able to partially restore CXCL12-induced chemotaxis in the J45.01 cells. However,
reconstitution of CD45 into the J45.01 cells restored the CXCL12-induced chemotaxis to about 90%. CD45 had no significant
effect on CXCL12 or human immunodeficiency virus gp120-induced internalization of the CXCR4 receptor. Furthermore, J45.01
cells showed a slight enhancement in CXCL12-induced MAP kinase activity as compared with the JE6.1 cells. We also observed
that CXCL12 treatment enhanced the tyrosine phosphorylation of CD45 and induced its association with the CXCR4 receptor. Pretreatment
of T-cells with the lipid raft inhibitor, methyl-β-cyclodextrin, blocked the association between CXCR4 and CD45 and markedly
abolished CXCL12-induced chemotaxis. Comparisons of signaling pathways induced by CXCL12 in JE6.1 and J45.01 cells revealed
that CD45 might moderately regulate the tyrosine phosphorylation of the focal adhesion components the related adhesion focal
tyrosine kinase/Pyk2, focal adhesion kinase, p130Cas, and paxillin. CD45 has also been shown to regulate CXCR4-mediated activation
and phosphorylation of T-cell receptor downstream effectors Lck, ZAP-70, and SLP-76. Our results show that CD45 differentially
regulates CXCR4-mediated chemotactic activity and MAPK activation by modulating the activities of focal adhesion components
and the downstream effectors of the T-cell receptor.</abstract><cop>United States</cop><pub>American Society for Biochemistry and Molecular Biology</pub><pmid>12519755</pmid><doi>10.1074/jbc.M211803200</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; EZB-FREE-00999 freely available EZB journals; Alma/SFX Local Collection |
| subjects | Adaptor Proteins, Signal Transducing Blotting, Western Cell Line Chemokine CXCL12 Chemokines, CXC - metabolism Chemotaxis Dose-Response Relationship, Drug Enzyme Activation Flow Cytometry Gene Expression Regulation Humans Jurkat Cells Leukocyte Common Antigens - metabolism Lymphocyte Specific Protein Tyrosine Kinase p56(lck) - metabolism Lymphocytes - metabolism MAP Kinase Signaling System Microscopy, Confocal Microscopy, Fluorescence Phosphoproteins - metabolism Phosphorylation Precipitin Tests Protein Structure, Tertiary Protein-Tyrosine Kinases - metabolism Receptors, Antigen, T-Cell - metabolism Receptors, CXCR4 - metabolism Signal Transduction T-Lymphocytes - metabolism Time Factors Tyrosine - metabolism ZAP-70 Protein-Tyrosine Kinase |
| title | Differential Regulation of CXCR4-mediated T-cell Chemotaxis and Mitogen-activated Protein Kinase Activation by the Membrane Tyrosine Phosphatase, CD45 |
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