SDF-1α/CXCR4 Signaling in Lipid Rafts Induces Platelet Aggregation via PI3 Kinase-Dependent Akt Phosphorylation
Stromal cell-derived factor-1α (SDF-1α)-induced platelet aggregation is mediated through its G protein-coupled receptor CXCR4 and phosphatidylinositol 3 kinase (PI3K). Here, we demonstrate that SDF-1α induces phosphorylation of Akt at Thr308 and Ser473 in human platelets. SDF-1α-induced platelet agg...
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| creator | Ohtsuka, Hiroko Iguchi, Tomohiro Hayashi, Moyuru Kaneda, Mizuho Iida, Kazuko Shimonaka, Motoyuki Hara, Takahiko Arai, Morio Koike, Yuichi Yamamoto, Naomasa Kasahara, Kohji |
| description | Stromal cell-derived factor-1α (SDF-1α)-induced platelet aggregation is mediated through its G protein-coupled receptor CXCR4 and phosphatidylinositol 3 kinase (PI3K). Here, we demonstrate that SDF-1α induces phosphorylation of Akt at Thr308 and Ser473 in human platelets. SDF-1α-induced platelet aggregation and Akt phosphorylation are inhibited by pretreatment with the CXCR4 antagonist AMD3100 or the PI3K inhibitor LY294002. SDF-1α also induces the phosphorylation of PDK1 at Ser241 (an upstream activator of Akt), GSK3β at Ser9 (a downstream substrate of Akt), and myosin light chain at Ser19 (a downstream element of the Akt signaling pathway). SDF-1α-induced platelet aggregation is inhibited by pretreatment with the Akt inhibitor MK-2206 in a dose-dependent manner. Furthermore, SDF-1α-induced platelet aggregation and Akt phosphorylation are inhibited by pretreatment with the raft-disrupting agent methyl-β-cyclodextrin. Sucrose density gradient analysis shows that 35% of CXCR4, 93% of the heterotrimeric G proteins Gαi-1, 91% of Gαi-2, 50% of Gβ and 4.0% of PI3Kβ, and 4.5% of Akt2 are localized in the detergent-resistant membrane raft fraction. These findings suggest that SDF-1α/CXCR4 signaling in lipid rafts induces platelet aggregation via PI3K-dependent Akt phosphorylation. |
| doi_str_mv | 10.1371/journal.pone.0169609 |
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Here, we demonstrate that SDF-1α induces phosphorylation of Akt at Thr308 and Ser473 in human platelets. SDF-1α-induced platelet aggregation and Akt phosphorylation are inhibited by pretreatment with the CXCR4 antagonist AMD3100 or the PI3K inhibitor LY294002. SDF-1α also induces the phosphorylation of PDK1 at Ser241 (an upstream activator of Akt), GSK3β at Ser9 (a downstream substrate of Akt), and myosin light chain at Ser19 (a downstream element of the Akt signaling pathway). SDF-1α-induced platelet aggregation is inhibited by pretreatment with the Akt inhibitor MK-2206 in a dose-dependent manner. Furthermore, SDF-1α-induced platelet aggregation and Akt phosphorylation are inhibited by pretreatment with the raft-disrupting agent methyl-β-cyclodextrin. Sucrose density gradient analysis shows that 35% of CXCR4, 93% of the heterotrimeric G proteins Gαi-1, 91% of Gαi-2, 50% of Gβ and 4.0% of PI3Kβ, and 4.5% of Akt2 are localized in the detergent-resistant membrane raft fraction. These findings suggest that SDF-1α/CXCR4 signaling in lipid rafts induces platelet aggregation via PI3K-dependent Akt phosphorylation.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0169609</identifier><identifier>PMID: 28072855</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>1-Phosphatidylinositol 3-kinase ; Agglomeration ; AKT protein ; AKT2 protein ; Biology and Life Sciences ; Blood platelets ; Blood Platelets - metabolism ; Cardiovascular disease ; Cell adhesion & migration ; Chemokine CXCL12 - metabolism ; CXCR4 protein ; Cyclodextrins ; Density gradients ; Downstream ; Humans ; Inhibitors ; Kinases ; Laboratories ; Lipid rafts ; Lipids ; Medicine and Health Sciences ; Membrane Microdomains - metabolism ; Methyl-β-Cyclodextrin ; Monoclonal antibodies ; Myosin ; Pharmaceutical sciences ; Phosphatidylinositol 3-Kinases - metabolism ; Phosphorylation ; Physical Sciences ; Platelet Aggregation ; Platelets ; Polyclonal antibodies ; Prostate ; Proteins ; Proto-Oncogene Proteins c-akt - metabolism ; Rafts ; Receptors, CXCR4 - metabolism ; Signal transduction ; Signaling ; Substrates ; Sucrose ; Sugar ; Thrombosis ; Whooping cough</subject><ispartof>PloS one, 2017-01, Vol.12 (1), p.e0169609-e0169609</ispartof><rights>2017 Ohtsuka et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 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These findings suggest that SDF-1α/CXCR4 signaling in lipid rafts induces platelet aggregation via PI3K-dependent Akt phosphorylation.</description><subject>1-Phosphatidylinositol 3-kinase</subject><subject>Agglomeration</subject><subject>AKT protein</subject><subject>AKT2 protein</subject><subject>Biology and Life Sciences</subject><subject>Blood platelets</subject><subject>Blood Platelets - metabolism</subject><subject>Cardiovascular disease</subject><subject>Cell adhesion & migration</subject><subject>Chemokine CXCL12 - metabolism</subject><subject>CXCR4 protein</subject><subject>Cyclodextrins</subject><subject>Density gradients</subject><subject>Downstream</subject><subject>Humans</subject><subject>Inhibitors</subject><subject>Kinases</subject><subject>Laboratories</subject><subject>Lipid rafts</subject><subject>Lipids</subject><subject>Medicine and Health Sciences</subject><subject>Membrane Microdomains - metabolism</subject><subject>Methyl-β-Cyclodextrin</subject><subject>Monoclonal antibodies</subject><subject>Myosin</subject><subject>Pharmaceutical sciences</subject><subject>Phosphatidylinositol 3-Kinases - metabolism</subject><subject>Phosphorylation</subject><subject>Physical Sciences</subject><subject>Platelet Aggregation</subject><subject>Platelets</subject><subject>Polyclonal antibodies</subject><subject>Prostate</subject><subject>Proteins</subject><subject>Proto-Oncogene Proteins c-akt - metabolism</subject><subject>Rafts</subject><subject>Receptors, CXCR4 - metabolism</subject><subject>Signal transduction</subject><subject>Signaling</subject><subject>Substrates</subject><subject>Sucrose</subject><subject>Sugar</subject><subject>Thrombosis</subject><subject>Whooping cough</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNptkt9u0zAUxiMEYn_gDRBY4oabdE5sx_EN0tQxqKhEtYHEneXYJ6lLagc7mbTH2ovwTKRtNm2IK1v273znO0dfkrzJ8CwjPDvb-CE41c4672CGs0IUWDxLjjNB8rTIMXn-6H6UnMS4wZiRsiheJkd5iXleMnacdNcXl2n25-5s_nN-RdG1bUZN6xpkHVrazhp0peo-ooUzg4aIVq3qoYUenTdNgEb11jt0YxVaLQj6ap2KkF5AB86AG6FfPVqtfezWPty2e_hV8qJWbYTX03ma_Lj89H3-JV1--7yYny9TzfKiT4WgHFMwtASqhcCGGsCFIbqiUIEhjGrMKg6C15QbTUzODKGZqVldclBATpN3B92u9VFOy4oyKxknBaaCjcTiQBivNrILdqvCrfTKyv2DD41Uobe6Bcl2i1MMGC4YJWWtcgBicFUVVCuh81Hr49RtqLZg9Dh8UO0T0ac_zq5l428ky3PK92Y-TALB_x4g9nJro4a2VQ78cPDNGRaEj-j7f9D_T0cPlA4-xgD1g5kMy12A7qvkLkByCtBY9vbxIA9F94khfwEF8cTQ</recordid><startdate>20170101</startdate><enddate>20170101</enddate><creator>Ohtsuka, Hiroko</creator><creator>Iguchi, Tomohiro</creator><creator>Hayashi, Moyuru</creator><creator>Kaneda, Mizuho</creator><creator>Iida, Kazuko</creator><creator>Shimonaka, Motoyuki</creator><creator>Hara, Takahiko</creator><creator>Arai, Morio</creator><creator>Koike, Yuichi</creator><creator>Yamamoto, Naomasa</creator><creator>Kasahara, Kohji</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</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>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20170101</creationdate><title>SDF-1α/CXCR4 Signaling in Lipid Rafts Induces Platelet Aggregation via PI3 Kinase-Dependent Akt Phosphorylation</title><author>Ohtsuka, Hiroko ; Iguchi, Tomohiro ; Hayashi, Moyuru ; Kaneda, Mizuho ; Iida, Kazuko ; Shimonaka, Motoyuki ; Hara, Takahiko ; Arai, Morio ; Koike, Yuichi ; Yamamoto, Naomasa ; Kasahara, Kohji</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c526t-994704ed48e4c990d4de06d3cb4ebed354c05b7e97f47dc3d25d341df5f87eae3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>1-Phosphatidylinositol 3-kinase</topic><topic>Agglomeration</topic><topic>AKT protein</topic><topic>AKT2 protein</topic><topic>Biology and Life Sciences</topic><topic>Blood platelets</topic><topic>Blood Platelets - metabolism</topic><topic>Cardiovascular disease</topic><topic>Cell adhesion & migration</topic><topic>Chemokine CXCL12 - metabolism</topic><topic>CXCR4 protein</topic><topic>Cyclodextrins</topic><topic>Density gradients</topic><topic>Downstream</topic><topic>Humans</topic><topic>Inhibitors</topic><topic>Kinases</topic><topic>Laboratories</topic><topic>Lipid rafts</topic><topic>Lipids</topic><topic>Medicine and Health Sciences</topic><topic>Membrane Microdomains - metabolism</topic><topic>Methyl-β-Cyclodextrin</topic><topic>Monoclonal antibodies</topic><topic>Myosin</topic><topic>Pharmaceutical sciences</topic><topic>Phosphatidylinositol 3-Kinases - metabolism</topic><topic>Phosphorylation</topic><topic>Physical Sciences</topic><topic>Platelet Aggregation</topic><topic>Platelets</topic><topic>Polyclonal antibodies</topic><topic>Prostate</topic><topic>Proteins</topic><topic>Proto-Oncogene Proteins c-akt - metabolism</topic><topic>Rafts</topic><topic>Receptors, CXCR4 - metabolism</topic><topic>Signal transduction</topic><topic>Signaling</topic><topic>Substrates</topic><topic>Sucrose</topic><topic>Sugar</topic><topic>Thrombosis</topic><topic>Whooping cough</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ohtsuka, Hiroko</creatorcontrib><creatorcontrib>Iguchi, Tomohiro</creatorcontrib><creatorcontrib>Hayashi, Moyuru</creatorcontrib><creatorcontrib>Kaneda, Mizuho</creatorcontrib><creatorcontrib>Iida, Kazuko</creatorcontrib><creatorcontrib>Shimonaka, Motoyuki</creatorcontrib><creatorcontrib>Hara, Takahiko</creatorcontrib><creatorcontrib>Arai, Morio</creatorcontrib><creatorcontrib>Koike, Yuichi</creatorcontrib><creatorcontrib>Yamamoto, Naomasa</creatorcontrib><creatorcontrib>Kasahara, Kohji</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Nursing & Allied Health Database</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Meteorological & Geoastrophysical Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Agricultural Science Collection</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Materials Science & Engineering Collection</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest One Sustainability</collection><collection>ProQuest Central UK/Ireland</collection><collection>Advanced Technologies & Aerospace Collection</collection><collection>Agricultural & Environmental Science Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Technology Collection</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Materials Science Collection</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Materials Science Database</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Meteorological & Geoastrophysical Abstracts - 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Here, we demonstrate that SDF-1α induces phosphorylation of Akt at Thr308 and Ser473 in human platelets. SDF-1α-induced platelet aggregation and Akt phosphorylation are inhibited by pretreatment with the CXCR4 antagonist AMD3100 or the PI3K inhibitor LY294002. SDF-1α also induces the phosphorylation of PDK1 at Ser241 (an upstream activator of Akt), GSK3β at Ser9 (a downstream substrate of Akt), and myosin light chain at Ser19 (a downstream element of the Akt signaling pathway). SDF-1α-induced platelet aggregation is inhibited by pretreatment with the Akt inhibitor MK-2206 in a dose-dependent manner. Furthermore, SDF-1α-induced platelet aggregation and Akt phosphorylation are inhibited by pretreatment with the raft-disrupting agent methyl-β-cyclodextrin. Sucrose density gradient analysis shows that 35% of CXCR4, 93% of the heterotrimeric G proteins Gαi-1, 91% of Gαi-2, 50% of Gβ and 4.0% of PI3Kβ, and 4.5% of Akt2 are localized in the detergent-resistant membrane raft fraction. These findings suggest that SDF-1α/CXCR4 signaling in lipid rafts induces platelet aggregation via PI3K-dependent Akt phosphorylation.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>28072855</pmid><doi>10.1371/journal.pone.0169609</doi><oa>free_for_read</oa></addata></record> |
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| issn | 1932-6203 1932-6203 |
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| subjects | 1-Phosphatidylinositol 3-kinase Agglomeration AKT protein AKT2 protein Biology and Life Sciences Blood platelets Blood Platelets - metabolism Cardiovascular disease Cell adhesion & migration Chemokine CXCL12 - metabolism CXCR4 protein Cyclodextrins Density gradients Downstream Humans Inhibitors Kinases Laboratories Lipid rafts Lipids Medicine and Health Sciences Membrane Microdomains - metabolism Methyl-β-Cyclodextrin Monoclonal antibodies Myosin Pharmaceutical sciences Phosphatidylinositol 3-Kinases - metabolism Phosphorylation Physical Sciences Platelet Aggregation Platelets Polyclonal antibodies Prostate Proteins Proto-Oncogene Proteins c-akt - metabolism Rafts Receptors, CXCR4 - metabolism Signal transduction Signaling Substrates Sucrose Sugar Thrombosis Whooping cough |
| title | SDF-1α/CXCR4 Signaling in Lipid Rafts Induces Platelet Aggregation via PI3 Kinase-Dependent Akt Phosphorylation |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-09T22%3A15%3A40IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=SDF-1%CE%B1/CXCR4%20Signaling%20in%20Lipid%20Rafts%20Induces%20Platelet%20Aggregation%20via%20PI3%20Kinase-Dependent%20Akt%20Phosphorylation&rft.jtitle=PloS%20one&rft.au=Ohtsuka,%20Hiroko&rft.date=2017-01-01&rft.volume=12&rft.issue=1&rft.spage=e0169609&rft.epage=e0169609&rft.pages=e0169609-e0169609&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0169609&rft_dat=%3Cproquest_plos_%3E4298282401%3C/proquest_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1857360495&rft_id=info:pmid/28072855&rft_doaj_id=oai_doaj_org_article_55386a5e5065438fa2ee3d0bb64ca9c2&rfr_iscdi=true |