{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T13:41:10Z","timestamp":1791639670074,"version":"4.3.4"},"reference-count":54,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2015,3,1]],"date-time":"2015-03-01T00:00:00Z","timestamp":1425168000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2015,3,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Chemokines engage B lymphocyte surface receptors, triggering heterotrimeric G protein G\u03b1i subunit guanine nucleotide exchange. RGS proteins limit the duration that G\u03b1i subunits remain GTP bound, and the loss of an individual RGS protein typically enhances chemokine receptor signaling. In this study, we show that B cells carrying a G\u03b1i2G184S\/G184S mutation that disables all RGS protein\/G\u03b1i2 interactions exhibit an unexpectedly severe reduction in chemokine receptor signaling. The G\u03b1i2G184S\/G184S B cells have markedly elevated basal calcium levels, but poor chemokine-induced increases, enhanced nonspecific migration, but extremely poor chemotaxis. In striking contrast, the G\u03b1i2G184S\/G184S B cells exhibited enhanced sensitivity to sphingosine 1-phosphate (S1P). S1P elicited heightened intracellular calcium responses and enhanced S1P-triggered cell migration. Mice with the G\u03b1i2G184S\/G184S mutation displayed excessive numbers of germinal center\u2013like structures; abnormal serum Ig profiles; and aberrant B lymphocyte trafficking. These findings establish an essential role for RGS proteins in B cell chemoattractant signaling and for the proper position of B lymphocytes in lymphoid organs.<\/jats:p>","DOI":"10.4049\/jimmunol.1401952","type":"journal-article","created":{"date-parts":[[2015,1,24]],"date-time":"2015-01-24T03:44:25Z","timestamp":1422071065000},"page":"2128-2139","source":"Crossref","is-referenced-by-count":29,"title":["An Essential Role for RGS Protein\/G\u03b1i2 Interactions in B Lymphocyte\u2013Directed Cell Migration and Trafficking"],"prefix":"10.1093","volume":"194","author":[{"given":"Il-Young","family":"Hwang","sequence":"first","affiliation":[{"name":"Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health , Bethesda, MD 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chung","family":"Park","sequence":"additional","affiliation":[{"name":"Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health , Bethesda, MD 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathleen","family":"Harrison","sequence":"additional","affiliation":[{"name":"Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health , Bethesda, MD 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cedric","family":"Boularan","sequence":"additional","affiliation":[{"name":"Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health , Bethesda, MD 20892"},{"name":"INSERM U1048, Institut des Maladies M\u00e9taboliques et Cardiovasculaires , 31432 Toulouse Cedex 4 ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C\u00e9line","family":"Gal\u00e9s","sequence":"additional","affiliation":[{"name":"INSERM U1048, Institut des Maladies M\u00e9taboliques et Cardiovasculaires , 31432 Toulouse Cedex 4 ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John H","family":"Kehrl","sequence":"additional","affiliation":[{"name":"Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health , Bethesda, MD 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2015,3,1]]},"reference":[{"key":"2025030705120803700_r1","doi-asserted-by":"crossref","first-page":"e72596","DOI":"10.1371\/journal.pone.0072596","article-title":"The loss of Gnai2 and Gnai3 in B cells eliminates B lymphocyte compartments and leads to a hyper-IgM like syndrome","volume":"8","author":"Hwang","year":"2013","journal-title":"PLoS One"},{"key":"2025030705120803700_r2","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1016\/S1074-7613(00)80046-1","article-title":"The chemokine receptor CXCR4 is required for the retention of B lineage and granulocytic precursors within the bone marrow microenvironment","volume":"10","author":"Ma","year":"1999","journal-title":"Immunity"},{"key":"2025030705120803700_r3","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1038\/ni.1710","article-title":"Cannabinoid receptor 2 mediates the retention of immature B cells in bone marrow sinusoids","volume":"10","author":"Pereira","year":"2009","journal-title":"Nat. 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Pharmacol."},{"key":"2025030705120803700_r44","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.gene.2010.12.001","article-title":"Comparative genomics uncovers novel structural and functional features of the heterotrimeric GTPase signaling system","volume":"475","author":"Anantharaman","year":"2011","journal-title":"Gene"},{"key":"2025030705120803700_r45","doi-asserted-by":"crossref","first-page":"7066","DOI":"10.1073\/pnas.0912934107","article-title":"Regulators of G-protein signaling accelerate GPCR signaling kinetics and govern sensitivity solely by accelerating GTPase activity","volume":"107","author":"Lambert","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025030705120803700_r46","doi-asserted-by":"crossref","first-page":"R313","DOI":"10.1016\/S0960-9822(98)70196-4","article-title":"G-protein signaling: fine-tuning signaling kinetics","volume":"8","author":"Zerangue","year":"1998","journal-title":"Curr. 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