{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T12:48:36Z","timestamp":1791204516374,"version":"4.2.0"},"reference-count":63,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2009,1,1]],"date-time":"2009-01-01T00:00:00Z","timestamp":1230768000000},"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":[[2009,1,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>The high efficiency of Ag processing and presentation by B cells requires Ag-induced BCR signaling and actin cytoskeleton reorganization, although the underlying mechanism for such requirements remains elusive. In this study, we identify Bruton\u2019s tyrosine kinase (Btk) as a linker connecting BCR signaling to actin dynamics and the Ag transport pathway. Using xid mice and a Btk inhibitor, we show that BCR engagement increases actin polymerization and Wiskott-Aldrich syndrome protein activation in a Btk-dependent manner. Concurrently, we observe Btk-dependent increases in the levels of phosphatidylinositide-4,5-bisphosphate and phosphorylated Vav upon BCR engagement. The rate of BCR internalization, its movement to late endosomes, and efficiency of BCR-mediated Ag processing and presentation are significantly reduced in both xid and Btk inhibitor-treated B cells. Thus, Btk regulates actin dynamics and Ag transport by activating Wiskott-Aldrich syndrome protein via Vav and phosphatidylinositides. This represents a novel mechanism by which BCR-mediated signaling regulates BCR-mediated Ag processing and presentation.<\/jats:p>","DOI":"10.4049\/jimmunol.182.1.329","type":"journal-article","created":{"date-parts":[[2014,4,18]],"date-time":"2014-04-18T23:17:12Z","timestamp":1397863032000},"page":"329-339","source":"Crossref","is-referenced-by-count":113,"title":["Btk Regulates B Cell Receptor-Mediated Antigen Processing and Presentation by Controlling Actin Cytoskeleton Dynamics in B Cells"],"prefix":"10.1093","volume":"182","author":[{"given":"Shruti","family":"Sharma","sequence":"first","affiliation":[{"name":"Department of Cell Biology and Molecular Genetics, University of Maryland , College Park, MD 20742"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory","family":"Orlowski","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Molecular Genetics, University of Maryland , College Park, MD 20742"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenxia","family":"Song","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Molecular Genetics, University of Maryland , College Park, MD 20742"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2009,1,1]]},"reference":[{"key":"2025032622112470400_R1","first-page":"107","article-title":"Floating the raft hypothesis: the roles of lipid rafts in B cell antigen receptor function.","volume-title":"Semin. Immunol.","year":"2001"},{"key":"2025032622112470400_R2","first-page":"453","article-title":"Initiation and processing of signals from the B cell antigen receptor.","volume-title":"Annu. Rev. Immunol.","year":"1997"},{"key":"2025032622112470400_R3","first-page":"4255","article-title":"Entry of B cell antigen receptor and antigen into class II peptide-loading compartment is independent of receptor cross-linking.","volume-title":"J. Immunol.","year":"1995"},{"key":"2025032622112470400_R4","first-page":"7171","article-title":"MHC class II antigen processing in B cells: accelerated intracellular targeting of antigens.","volume-title":"J. Immunol.","year":"1999"},{"key":"2025032622112470400_R5","first-page":"2127","article-title":"Receptor facilitated antigen presentation requires the recruitment of B cell linker protein to Ig\u03b1.","volume-title":"J. Immunol.","year":"2002"},{"key":"2025032622112470400_R6","first-page":"3451","article-title":"Syk-dependent actin dynamics regulate endocytic trafficking and processing of antigens internalized through the B-cell receptor.","volume-title":"Mol. Biol. Cell","year":"2007"},{"key":"2025032622112470400_R7","first-page":"57","article-title":"Epstein-Barr virus coopts lipid rafts to block the signaling and antigen transport functions of the BCR.","volume-title":"Immunity","year":"2001"},{"key":"2025032622112470400_R8","first-page":"1","article-title":"Signaling through the B cell antigen receptor regulates discrete steps in the antigen processing pathway.","volume-title":"Cell. Immunol.","year":"1998"},{"key":"2025032622112470400_R9","first-page":"1507","article-title":"Visualization of Syk-antigen receptor interactions using green fluorescent protein: differential roles for Syk and Lyn in the regulation of receptor capping and internalization.","volume-title":"J. Immunol.","year":"2001"},{"key":"2025032622112470400_R10","first-page":"451","article-title":"Lipid rafts unite signaling cascades with clathrin to regulate BCR internalization.","volume-title":"Immunity","year":"2002"},{"key":"2025032622112470400_R11","first-page":"1096","article-title":"Cross-linking of the IgM receptor induces rapid translocation of IgM-associated Ig\u03b1, Lyn, and Syk tyrosine kinases to the membrane skeleton.","volume-title":"J. Immunol.","year":"1997"},{"key":"2025032622112470400_R12","first-page":"3915","article-title":"Membrane Ig-cytoskeletal interactions, I: flow cytofluorometric and biochemical analysis of membrane IgM-cytoskeletal interactions.","volume-title":"J. Immunol.","year":"1988"},{"key":"2025032622112470400_R13","first-page":"1139","article-title":"Microfilament assembly is required for antigen-receptor-mediated activation of human B lymphocytes.","volume-title":"J. Immunol.","year":"1991"},{"key":"2025032622112470400_R14","first-page":"1424","article-title":"Tyrosine phosphorylation is essential for microfilament assembly in B lymphocytes.","volume-title":"Biochem. Biophys. Res. Commun.","year":"1991"},{"key":"2025032622112470400_R15","first-page":"3693","article-title":"Translocation of the B cell antigen receptor into lipid rafts reveals a novel step in signaling.","volume-title":"J. Immunol.","year":"2001"},{"key":"2025032622112470400_R16","first-page":"414","article-title":"The actin cytoskeleton is required for the trafficking of the B cell antigen receptor to the late endosomes.","volume-title":"Traffic","year":"2001"},{"key":"2025032622112470400_R17","first-page":"2339","article-title":"Plasticity of B cell receptor internalization upon conditional depletion of clathrin.","volume-title":"Mol. Biol. Cell","year":"2005"},{"key":"2025032622112470400_R18","first-page":"198","article-title":"The Wiskott-Aldrich syndrome protein (WASP) family.","volume-title":"Trends Biochem. Sci.","year":"2001"},{"key":"2025032622112470400_R19","first-page":"635","article-title":"WASp in immune-system organization and function.","volume-title":"Nat. Rev. Immunol.","year":"2002"},{"key":"2025032622112470400_R20","first-page":"45115","article-title":"Phosphorylation of tyrosine 291 enhances the ability of WASp to stimulate actin polymerization and filopodium formation. Wiskott-Aldrich Syndrome protein.","volume-title":"J. Biol. Chem.","year":"2002"},{"key":"2025032622112470400_R21","first-page":"42219","article-title":"Phosphorylation of WASP by the Cdc42-associated kinase ACK1: dual hydroxyamino acid specificity in a tyrosine kinase.","volume-title":"J. Biol. Chem.","year":"2005"},{"key":"2025032622112470400_R22","first-page":"1229","article-title":"Phosphorylation of the WASP-VCA domain increases its affinity for the Arp2\/3 complex and enhances actin polymerization by WASP.","volume-title":"Mol. Cell.","year":"2003"},{"key":"2025032622112470400_R23","first-page":"1311","article-title":"Activation by Cdc42 and PIP2 of Wiskott-Aldrich syndrome protein (WASp) stimulates actin nucleation by Arp2\/3 complex.","volume-title":"J. Cell Biol.","year":"2000"},{"key":"2025032622112470400_R24","first-page":"1196","article-title":"Tyrosine phosphorylation of the vav proto-oncogene product in activated B cells.","volume-title":"Science","year":"1992"},{"key":"2025032622112470400_R25","first-page":"88","article-title":"Activation of the small GTPase Rac2 via the B cell receptor regulates B cell adhesion and immunological-synapse formation.","volume-title":"Immunity","year":"2008"},{"key":"2025032622112470400_R26","first-page":"635","article-title":"CD19 as a membrane-anchored adaptor protein of B lymphocytes: costimulation of lipid and protein kinases by recruitment of Vav.","volume-title":"Immunity","year":"1998"},{"key":"2025032622112470400_R27","first-page":"200","article-title":"Bruton\u2019s tyrosine kinase: cell biology, sequence conservation, mutation spectrum, siRNA modifications, and expression profiling.","volume-title":"Immunol. Rev.","year":"2005"},{"key":"2025032622112470400_R28","first-page":"120","article-title":"The role of Bruton\u2019s tyrosine kinase in B-cell development and function: a genetic perspective.","volume-title":"Immunol. Rev.","year":"2000"},{"key":"2025032622112470400_R29","first-page":"6241","article-title":"Distinct specificity in the recognition of phosphoinositides by the pleckstrin homology domains of dynamin and Bruton\u2019s tyrosine kinase.","volume-title":"EMBO J.","year":"1996"},{"key":"2025032622112470400_R30","first-page":"515","article-title":"Regulation of Btk function by a major autophosphorylation site within the SH3 domain.","volume-title":"Immunity","year":"1996"},{"key":"2025032622112470400_R31","first-page":"822","article-title":"Activation of BTK by a phosphorylation mechanism initiated by SRC family kinases.","volume-title":"Science","year":"1996"},{"key":"2025032622112470400_R32","first-page":"1","article-title":"BLNK: connecting Syk and Btk to calcium signals.","volume-title":"Immunity","year":"2000"},{"key":"2025032622112470400_R33","first-page":"669","article-title":"BTK regulates PtdIns-4,5-P2 synthesis: importance for calcium signaling and PI3K activity.","volume-title":"Immunity","year":"2003"},{"key":"2025032622112470400_R34","first-page":"16201","article-title":"Interaction between the Btk PH domain and phosphatidylinositol-3,4,5-trisphosphate directly regulates Btk.","volume-title":"J. Biol. Chem.","year":"2001"},{"key":"2025032622112470400_R35","first-page":"10983","article-title":"Phosphatidylinositol 3-kinase-dependent membrane association of the Bruton\u2019s tyrosine kinase pleckstrin homology domain visualized in single living cells.","volume-title":"J. Biol. Chem.","year":"1999"},{"key":"2025032622112470400_R36","first-page":"1619","article-title":"Itk functions to control actin polymerization at the immune synapse through localized activation of Cdc42 and WASP.","volume-title":"Curr. Biol.","year":"2003"},{"key":"2025032622112470400_R37","first-page":"638","article-title":"Requirement for Tec kinases Rlk and Itk in T cell receptor signaling and immunity.","volume-title":"Science","year":"1999"},{"key":"2025032622112470400_R38","first-page":"375","article-title":"Measurement of co-localization of object in dual-colour confocal images.","volume-title":"J. Microsc.","year":"1993"},{"key":"2025032622112470400_R39","first-page":"199","article-title":"EGF stimulates an increase in actin nucleation and filament number at the leading edge of the lamellipod in mammary adenocarcinoma cells.","volume-title":"J. Cell. Sci.","year":"1998"},{"key":"2025032622112470400_R40","first-page":"3972","article-title":"Measurement of ligand-induced activation in single viable T cells using the lacZ reporter gene.","volume-title":"Proc. Natl. Acad. Sci. USA","year":"1991"},{"key":"2025032622112470400_R41","first-page":"369","article-title":"LacZ inducible, antigen\/MHC-specific T cell hybrids.","volume-title":"Int. Immunol.","year":"1994"},{"key":"2025032622112470400_R42","first-page":"9587","article-title":"Rational design and synthesis of a novel anti-leukemic agent targeting Bruton\u2019s tyrosine kinase (BTK), LFM-A13 [\u03b1-cyano-\u03b2-hydroxy-\u03b2-methyl-N-(2, 5-dibromophenyl)propenamide].","volume-title":"J. Biol. Chem.","year":"1999"},{"key":"2025032622112470400_R43","first-page":"6573","article-title":"Recognition and activation of Rho GTPases by Vav1 and Vav2 guanine nucleotide exchange factors.","volume-title":"Biochemistry","year":"2005"},{"key":"2025032622112470400_R44","first-page":"1678","article-title":"Tyrosine phosphorylation mediates both activation and downmodulation of the biological activity of Vav.","volume-title":"Mol. Cell. Biol.","year":"2000"},{"key":"2025032622112470400_R45","first-page":"13856","article-title":"Production, specificity, and functionality of monoclonal antibodies to specific peptide-major histocompatibility complex class II complexes formed by processing of exogenous protein.","volume-title":"Proc. Natl. Acad. Sci. USA","year":"1997"},{"key":"2025032622112470400_R46","first-page":"2275","article-title":"Actin depolymerization transduces the strength of B-cell receptor stimulation.","volume-title":"Mol. Biol. Cell","year":"2005"},{"key":"2025032622112470400_R47","first-page":"309","article-title":"Btk function in B cell development and response.","volume-title":"Semin. Immunol.","year":"1998"},{"key":"2025032622112470400_R48","first-page":"409","article-title":"The Btk inhibitor LFM-A13 is a potent inhibitor of Jak2 kinase activity.","volume-title":"Biol. Chem.","year":"2004"},{"key":"2025032622112470400_R49","first-page":"2851","article-title":"Engagement of the B-cell antigen receptor activates STAT through Lyn in a Jak-independent pathway.","volume-title":"Oncogene","year":"2007"},{"key":"2025032622112470400_R50","first-page":"2003","article-title":"Involvement of wiskott-aldrich syndrome protein in B-cell cytoplasmic tyrosine kinase pathway.","volume-title":"Blood","year":"1999"},{"key":"2025032622112470400_R51","first-page":"3791","article-title":"Evidence that the Wiskott-Aldrich syndrome protein may be involved in lymphoid cell signaling pathways.","volume-title":"J. Immunol.","year":"1996"},{"key":"2025032622112470400_R52","first-page":"2269","article-title":"The SH3 domain of Bruton\u2019s tyrosine kinase displays altered ligand binding properties when auto-phosphorylated in vitro.","volume-title":"Eur. J. Immunol.","year":"1999"},{"key":"2025032622112470400_R53","first-page":"5923","article-title":"Tec kinases regulate TCR-mediated recruitment of signaling molecules and integrin-dependent cell adhesion.","volume-title":"J. Immunol.","year":"2005"},{"key":"2025032622112470400_R54","first-page":"30644","article-title":"Syk and Bruton\u2019s tyrosine kinase are required for B cell antigen receptor-mediated activation of the kinase Akt.","volume-title":"J. Biol. Chem.","year":"1999"},{"key":"2025032622112470400_R55","first-page":"1973","article-title":"Btk\/Tec kinases regulate sustained increases in intracellular Ca2+ following B-cell receptor activation.","volume-title":"EMBO J.","year":"1998"},{"key":"2025032622112470400_R56","first-page":"260","article-title":"Bruton\u2019s tyrosine kinase regulates B cell antigen receptor-mediated JNK1 response through Rac1 and phospholipase C-\u03b32 activation.","volume-title":"FEBS Lett.","year":"2002"},{"key":"2025032622112470400_R57","first-page":"113","article-title":"Signalling of Bruton\u2019s tyrosine kinase, Btk.","volume-title":"Scand. J. Immunol.","year":"1999"},{"key":"2025032622112470400_R58","first-page":"1194","article-title":"Role of accessory cells in B cell activation. III. Cellular analysis of primary immune response deficits in CBA\/N mice: presence of an accessory cell-B cell interaction defect.","volume-title":"J. Exp. Med.","year":"1980"},{"key":"2025032622112470400_R59","first-page":"81","article-title":"Wiskott-Aldrich syndrome protein-deficient mice reveal a role for WASP in T but not B cell activation.","volume-title":"Immunity","year":"1998"},{"key":"2025032622112470400_R60","first-page":"309","article-title":"Regulation of actin dynamics by WASP family proteins.","volume-title":"J. Biochem.","year":"2003"},{"key":"2025032622112470400_R61","first-page":"33413","article-title":"Syk-mediated tyrosine phosphorylation is required for the association of hematopoietic lineage cell-specific protein 1 with lipid rafts and B cell antigen receptor signalosome complex.","volume-title":"J. Biol. Chem.","year":"2004"},{"key":"2025032622112470400_R62","first-page":"6685","article-title":"Actin-binding protein 1 regulates B cell receptor-mediated antigen processing and presentation in response to B cell receptor activation.","volume-title":"J. Immunol.","year":"2008"},{"key":"2025032622112470400_R63","first-page":"1611","article-title":"Severe B cell deficiency in mice lacking the tec kinase family members Tec and Btk.","volume-title":"J. Exp. Med.","year":"2000"}],"container-title":["The Journal of Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/182\/1\/329\/62681202\/8330.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/182\/1\/329\/62681202\/8330.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,29]],"date-time":"2025-03-29T20:15:21Z","timestamp":1743279321000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jimmunol\/article\/182\/1\/329\/8004458"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2009,1,1]]},"references-count":63,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2009,1,1]]}},"URL":"https:\/\/doi.org\/10.4049\/jimmunol.182.1.329","relation":{},"ISSN":["1550-6606","0022-1767"],"issn-type":[{"value":"1550-6606","type":"electronic"},{"value":"0022-1767","type":"print"}],"subject":[],"published-other":{"date-parts":[[2009,1]]},"published":{"date-parts":[[2009,1,1]]}}}