title: A balance of Bruton's tyrosine kinase and SHIP activation regulates B cell receptor cluster formation by controlling actin remodeling.
abstract: The activation of the BCR, which initiates B cell activation, is triggered by Ag-induced self-aggregation and clustering of receptors at the cell surface. Although Ag-induced actin reorganization is known to be involved in BCR clustering in response to membrane-associated Ag, the underlying mechanism that links actin reorganization to BCR activation remains unknown. In this study, we show that both the stimulatory Bruton's tyrosine kinase (Btk) and the inhibitory SHIP-1 are required for efficient BCR self-aggregation. In Btk-deficient B cells, the magnitude of BCR aggregation into clusters and B cell spreading in response to an Ag-tethered lipid bilayer is drastically reduced, compared with BCR aggregation observed in wild-type B cells. In SHIP-1(-/-) B cells, although surface BCRs aggregate into microclusters, the centripetal movement and growth of BCR clusters are inhibited, and B cell spreading is increased. The persistent BCR microclusters in SHIP-1(-/-) B cells exhibit higher levels of signaling than merged BCR clusters. In contrast to the inhibition of actin remodeling in Btk-deficient B cells, actin polymerization, F-actin accumulation, and Wiskott-Aldrich symptom protein phosphorylation are enhanced in SHIP-1(-/-) B cells in a Btk-dependent manner. Thus, a balance between positive and negative signaling regulates the spatiotemporal organization of the BCR at the cell surface by controlling actin remodeling, which potentially regulates the signal transduction of the BCR. This study suggests a novel feedback loop between BCR signaling and the actin cytoskeleton.
authors.affiliation: Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD 20742, USA.
authors.forename: Chaohong
authors.initials: C
authors.lastname: Liu
authors.forename: Heather
authors.initials: H
authors.lastname: Miller
authors.forename: King Lam
authors.initials: KL
authors.lastname: Hui
authors.forename: Brian
authors.initials: B
authors.lastname: Grooman
authors.forename: Silvia
authors.initials: S
authors.lastname: Bolland
authors.forename: Arpita
authors.initials: A
authors.lastname: Upadhyaya
authors.forename: Wenxia
authors.initials: W
authors.lastname: Song
mesh_terms: D000199:Actins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D016175:B-Lymphocyte Subsets / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D004789:Enzyme Activation / Q000235:genetics / Q000276:immunology; D000072181:Inositol Polyphosphate 5-Phosphatases; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D008822:Mice, Transgenic; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism* / Q000502:physiology; D011947:Receptors, Antigen, B-Cell / Q000096:biosynthesis / Q000378:metabolism*; D051316:Wiskott-Aldrich Syndrome Protein / Q000378:metabolism
chemical_list: D000199:Actins; D011947:Receptors, Antigen, B-Cell; C495767:WAS protein, human; D051316:Wiskott-Aldrich Syndrome Protein; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; C000625951:Btk protein, mouse; D010744:Phosphoric Monoester Hydrolases; D000072181:Inositol Polyphosphate 5-Phosphatases; C000606430:INPP5D protein, human; C000606433:Inpp5d protein, mouse; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases