The fate of B cells is highly dependent on signals from the B cell antigen receptor (BCR) for development, tolerance, and activation decisions. The overall goal of this project is to understand the role of cholesterol- rich subdomains of the plasma membrane called lipid rafts in BCR signal transduction. Recent work in B cells has established that lipid rafts play a role in BCR signaling. Lipid rafts exist primarily as small, highly dynamic structures that coalesce into larger and more stable lipid rafts upon cell stimulation. BCR stimulation leads to its movement from the non-lipid raft plasma membrane into lipid rafts and induces coalescence of lipid rafts, eventually leading to a large lipid raft patch or cap on the cell surface.
In Specific Aim 1, the mechanism of BCR-induced lipid raft coalescence will be studied. BCR stimulation causes ezrin to become dephosphorylated and to release its connection between some lipid raft proteins and the actin cytoskeleton. We shall test if this release promotes lipid raft coalescence and BCR signaling. We hypothesize that the later stages of lipid raft coalescence require active processes involving myosins and will attempt to identify the myosin isoform responsible. BCR stimulation also leads to outgrowth of long filopdia- like projections (""""""""cytonemes"""""""") and in Specific Aim 2, we shall determine the mechanism of outgrowth of these projections. We shall explore the role of the B144 protein, the Rac1 and Cdc42 GTPases, and myosin 10 and its close relatives.
In Specific Aim 3, we shall examine the connection of lipid rafts to the ability of the BCR to activate the key transcription factor, NF-kB. Carmal, a key scaffold molecule for this signaling pathway, is localized to lipid rafts and it recruits other components of this pathway to lipid rafts following BCR stimulation. The importance of Carmal localization to lipid rafts and of lipid raft coalescence for activation of NF-kB will be determined. Finally, in Specific Aim 4, we shall examine lipid raft coalescence and NF-kB pathway activation in immature B cells and B cell lines'of immature phenotype, which appear to differ from mature B cells in these processes. . Lay Language Statement: The ability of the immune system to respond to infectious agents depends on the function of the antigen receptors of lymphocytes. This function appears to involve changes in a subdomain of the plasma membrane called lipid rafts and the mechanisms of these changes will be studied.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
Cellular and Molecular Immunology - B (CMI)
Program Officer
Ferguson, Stacy E
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California San Francisco
Schools of Medicine
San Francisco
United States
Zip Code
Proekt, Irina; Miller, Corey N; Jeanne, Marion et al. (2016) LYN- and AIRE-mediated tolerance checkpoint defects synergize to trigger organ-specific autoimmunity. J Clin Invest 126:3758-3771
Wheeler, Matthew L; Dong, Matthew B; Brink, Robert et al. (2013) Diacylglycerol kinase ? limits B cell antigen receptor-dependent activation of ERK signaling to inhibit early antibody responses. Sci Signal 6:ra91
Wheeler, Matthew L; Defranco, Anthony L (2012) Prolonged production of reactive oxygen species in response to B cell receptor stimulation promotes B cell activation and proliferation. J Immunol 189:4405-16
Shahaf, Gitit; Gross, Andrew J; Sternberg-Simon, Michal et al. (2012) Lyn deficiency affects B-cell maturation as well as survival. Eur J Immunol 42:511-21
Gross, Andrew J; Proekt, Irina; DeFranco, Anthony L (2011) Elevated BCR signaling and decreased survival of Lyn-deficient transitional and follicular B cells. Eur J Immunol 41:3645-55
Gross, Andrew J; Lyandres, Julia R; Panigrahi, Anil K et al. (2009) Developmental acquisition of the Lyn-CD22-SHP-1 inhibitory pathway promotes B cell tolerance. J Immunol 182:5382-92
Gupta, Neetu; Wollscheid, Bernd; Watts, Julian D et al. (2006) Quantitative proteomic analysis of B cell lipid rafts reveals that ezrin regulates antigen receptor-mediated lipid raft dynamics. Nat Immunol 7:625-33
Nishiya, Tadashi; Kajita, Emi; Miwa, Soichi et al. (2005) TLR3 and TLR7 are targeted to the same intracellular compartments by distinct regulatory elements. J Biol Chem 280:37107-17
Tian, Maoxin Tim; Gonzalez, Gabriel; Scheer, Barbara et al. (2005) Bcl10 can promote survival of antigen-stimulated B lymphocytes. Blood 106:2105-12
Nishiya, Tadashi; DeFranco, Anthony L (2004) Ligand-regulated chimeric receptor approach reveals distinctive subcellular localization and signaling properties of the Toll-like receptors. J Biol Chem 279:19008-17

Showing the most recent 10 out of 49 publications