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Phospholipase C-2 and Vav cooperate within signaling microclusters to propagate B cell spreading in response to membrane-bound antigen

¹ Lymphocyte Interaction Laboratory, London Research Institute, Cancer Research UK, London WC2A 3PX, England, UK
² Laboratory for Lymphocyte Differentiation, RIKEN Research Center for Allergy and Immunology, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan

CORRESPONDENCE Facundo D. Batista: facundo.batista{at}cancer.org.uk

B cell receptor (BCR) recognition of membrane-bound antigen initiates a spreading and contraction response, the extent of which is controlled through the formation of signaling-active BCR-antigen microclusters and ultimately affects the outcome of B cell activation. We followed a genetic approach to define the molecular requirements of BCR-induced spreading and microcluster formation. We identify a key role for phospholipase C-2 (PLC2), Vav, B cell linker, and Bruton's tyrosine kinase in the formation of highly coordinated "microsignalosomes," the efficient assembly of which is absolutely dependent on Lyn and Syk. Using total internal reflection fluorescence microscopy, we examine at high resolution the recruitment of PLC2 and Vav to microsignalosomes, establishing a novel synergistic relationship between the two. Thus, we demonstrate the importance of cooperation between components of the microsignalosome in the amplification of signaling and propagation of B cell spreading, which is critical for appropriate B cell activation.

Abbreviations used: BCAP, B cell adaptor for PI3K; Blnk, B cell linker; Btk, Bruton's tyrosine kinase; cSMAC, central supramolecular activation cluster; DIC, differential interference contrast; EGFP, enhanced GFP; GEF, guanine nucleotide exchange factor; HEL, hen egg lysozyme; IP₃, inositol 1,4,5-triphosphate; IRM, interference reflection microscopy; IS, immunological synapse; PI3K, phosphoinositide 3-kinase; PIP₂, phosphatidylinositol bisphosphate; PKCβ, protein kinase C-β; PLC2, phospholipase C-2; PLC2-LD, PLC2 with lipase-defective activity; SEM, scanning electron microscopy; SH2, Src homology 2; TIRFM, total internal reflection fluorescence microscopy; Vav1/2-KO, Vav1 and Vav2 knockout.

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