B cell activation is initiated by tyrosine phosphorylation of proximal cytosolic and membrane bound adaptor proteins to allow branching of signaling pathways, such as the phosphatidylinositol 3-kinase (PI3K) pathway. Phosphoinositide metabolism is thought to be of key importance to aspects of B cell activation, proliferation, differentiation and survival. PI3K activity is induced by the BCR and amplified by p85alpha recruitment to CD19 and perhaps other cytosolic adaptor proteins. Phosphatidylinositol-3,4,5-trisphosphate (PIP3,4,5) is generated by PI3K in activated cells, leading to the recruitment of pleckstrin-homology (PH)-containing proteins and conformation induced activation of other binding partners, Excessive production of PIP3,4,5 leads to autoimmunity or transformation and is tightly regulated by the inositol phosphatases PTEN and SHIP. The overall goal of this renewal is to understand the context of PIP3,4,5 regulation in B cell differentiation and maintenance. Central to this goal is a detailed understanding of phosphoinositide metabolism in B cells with a particular focus on the opposing enzymatic activities of PI3-kinase, PTEN and SHIP in regulating levels of PIP3,4, 5 and its incumbent role in the recruitment and activation of signaling intermediates. CD19 is the primary activator of PI3K in B cells, leading to the production of PIP3,4 and PIP3,4,5, while the inositol phosphatase PTEN acts to attenuate PIP3,4,5 accumulation by conversion to PIP4,5. Fc-gamma-RIIB1 (CD32) can also attenuate PIP3,4,5 levels through the recruitment of SHIP phosphatase, which converts PIP3,4,5 to PIP3,4. These findings suggest an interplay of CD19 and CD32 function focused on the regulated production of PIP3,4,5 and its ability to recruit and activate downstream effectors. Herein we explore the molecular basis and physiologic significance of CD19 and CD32 function in the regulated production of PIP3,4, PIP4,5 and PIP3,4,5 as key secondary messengers to effect cell fate.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Immunobiology Study Section (IMB)
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Ferguson, Stacy E
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Sanford-Burnham Medical Research Institute
La Jolla
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Jellusova, Julia; Cato, Matthew H; Apgar, John R et al. (2017) Gsk3 is a metabolic checkpoint regulator in B cells. Nat Immunol 18:303-312
Lee, Peishan; Zhu, Zilu; Hachmann, Janna et al. (2017) Differing Requirements for MALT1 Function in Peripheral B Cell Survival and Differentiation. J Immunol 198:1066-1080
Boothby, Mark; Rickert, Robert C (2017) Metabolic Regulation of the Immune Humoral Response. Immunity 46:743-755
Ramezani-Rad, Parham; Rickert, Robert C (2017) Murine models of germinal center derived-lymphomas. Curr Opin Immunol 45:31-36
McAllister, Ellen J; Apgar, John R; Leung, Charlotte R et al. (2017) New Methods To Analyze B Cell Immune Responses to Thymus-Dependent Antigen Sheep Red Blood Cells. J Immunol 199:2998-3003
Jellusova, Julia; Rickert, Robert C (2016) The PI3K pathway in B cell metabolism. Crit Rev Biochem Mol Biol 51:359-378
Miletic, Ana V; Jellusova, Julia; Cato, Matthew H et al. (2016) Essential Role for Survivin in the Proliferative Expansion of Progenitor and Mature B Cells. J Immunol 196:2195-204
Baracho, Gisele V; Cato, Matthew H; Zhu, Zilu et al. (2014) PDK1 regulates B cell differentiation and homeostasis. Proc Natl Acad Sci U S A 111:9573-8
Luo, Wei; Mayeux, Jessica; Gutierrez, Toni et al. (2014) A balance between B cell receptor and inhibitory receptor signaling controls plasma cell differentiation by maintaining optimal Ets1 levels. J Immunol 193:909-920
Jellusova, Julia; Miletic, Ana V; Cato, Matthew H et al. (2013) Context-specific BAFF-R signaling by the NF-?B and PI3K pathways. Cell Rep 5:1022-35

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