{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T19:52:39Z","timestamp":1789588359827,"version":"build-2803163510"},"reference-count":57,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2022,9,29]],"date-time":"2022-09-29T00:00:00Z","timestamp":1664409600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Comprehensive Cancer Center at UC Davis School of Medicine","award":["P30CA093373"],"award-info":[{"award-number":["P30CA093373"]}]},{"name":"UC Davis Comprehensive Cancer Center Support Grant (CCSG) awarded by the National Cancer Institute","award":["P30CA093373"],"award-info":[{"award-number":["P30CA093373"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Activation of platelet integrin \u03b1IIb\u03b23, a key event for hemostasis and thrombus formation, is known to be mediated exclusively by inside-out signaling. We showed that inflammatory chemokines CX3CL1 and CXCL12 in previous studies, and CCL5 in this study, bound to the allosteric binding site (site 2) of vascular integrin \u03b1v\u03b23, in addition to the classical ligand binding site (site 1), and allosterically activated integrins independent of inside-out signaling. Since \u03b1IIb\u03b23 is exposed to inflammatory chemokines at increased concentrations during inflammation (e.g., cytokine\/chemokine storm) and platelet activation, we hypothesized that these chemokines bind to and activate \u03b1IIb\u03b23 in an allosteric activation mechanism. We found that these chemokines bound to \u03b1IIb\u03b23. Notably, they activated soluble \u03b1IIb\u03b23 in 1 mM Ca2+ by binding to site 2. They activated cell-surface \u03b1IIb\u03b23 on CHO cells, which lack machinery for inside-out signaling or chemokine receptors, quickly (&lt;1 min) and at low concentrations (1\u201310 ng\/mL) compared to activation of soluble \u03b1IIb\u03b23, probably because chemokines bind to cell surface proteoglycans. Furthermore, activation of \u03b1IIb\u03b23 by the chemokines was several times more potent than 1 mM Mn2+. We propose that CCL5 and CXCL12 (stored in platelet granules) may allosterically activate \u03b1IIb\u03b23 upon platelet activation and trigger platelet aggregation. Transmembrane CX3CL1 on activated endothelial cells may mediate platelet\u2013endothelial interaction by binding to and activating \u03b1IIb\u03b23. Additionally, these chemokines in circulation over-produced during inflammation may trigger \u03b1IIb\u03b23 activation, which is a possible missing link between inflammation and thrombosis.<\/jats:p>","DOI":"10.3390\/cells11193059","type":"journal-article","created":{"date-parts":[[2022,9,29]],"date-time":"2022-09-29T21:03:10Z","timestamp":1664485390000},"page":"3059","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Pro-Inflammatory Chemokines CCL5, CXCL12, and CX3CL1 Bind to and Activate Platelet Integrin \u03b1IIb\u03b23 in an Allosteric Manner"],"prefix":"10.3390","volume":"11","author":[{"given":"Yoko K.","family":"Takada","sequence":"first","affiliation":[{"name":"Department of Dermatology, School of Medicine, University of California\u2013Davis, 4645 Second Ave., Research III Suite 3300, Sacramento, CA 95817, USA"},{"name":"Department of Biochemistry and Molecular Medicine, University of California Davis School of Medicine, Sacramento, CA 95817, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masaaki","family":"Fujita","sequence":"additional","affiliation":[{"name":"Department of Dermatology, School of Medicine, University of California\u2013Davis, 4645 Second Ave., Research III Suite 3300, Sacramento, CA 95817, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshikazu","family":"Takada","sequence":"additional","affiliation":[{"name":"Department of Dermatology, School of Medicine, University of California\u2013Davis, 4645 Second Ave., Research III Suite 3300, Sacramento, CA 95817, USA"},{"name":"Department of Biochemistry and Molecular Medicine, University of California Davis School of Medicine, Sacramento, CA 95817, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,9,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"18066","DOI":"10.1074\/jbc.M801213200","article-title":"Direct Binding of Integrin Alphavbeta3 to Fgf1 Plays a Role in Fgf1 Signaling","volume":"283","author":"Mori","year":"2008","journal-title":"J. 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