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Basal B cell receptor-directed phosphatidylinositol 3-kinase signaling turns off rags and promotes B cell-positive selection

Academic Article
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Overview

related to degree

  • Duong, Bao Hoa, Ph.D. in Macromolecular and Cellular Structure and Chemistry, Scripps Research 2003 - 2009
  • Vela, Jose L, Ph.D. in Immunology, Scripps Research 2001 - 2007

authors

  • Verkoczy, L.
  • Duong, Bao Hoa
  • Skog, P.
  • Ait-Azzouzene, D.
  • Puri, K.
  • Vela, Jose L
  • Nemazee, David

publication date

  • May 2007

journal

  • Journal of Immunology  Journal

abstract

  • PI3K plays key roles in cell growth, differentiation, and survival by generating the second messenger phosphatidylinositol-(3,4,5)-trisphosphate (PIP3). PIP3 activates numerous enzymes, in part by recruiting them from the cytosol to the plasma membrane. We find that in immature B lymphocytes carrying a nonautoreactive Ag receptor, PI3K signaling suppresses RAG expression and promotes developmental progression. Inhibitors of PI3K signaling abrogate this positive selection. Furthermore, immature primary B cells from mice lacking the p85alpha regulatory subunit of PI3K suppress poorly RAG expression, undergo an exaggerated receptor editing response, and, as in BCR-ligated cells, fail to progress into the G1 phase of cell cycle. Moreover, immature B cells carrying an innocuous receptor have sustained elevation of PIP3 levels and activation of the downstream effectors phospholipase C (PLC)gamma2, Akt, and Bruton's tyrosine kinase. Of these, PLCgamma2 appears to play the most significant role in down-regulating RAG expression. It therefore appears that when the BCR of an immature B cell is ligated, PIP3 levels are reduced, PLCgamma2 activation is diminished, and receptor editing is promoted by sustained RAG expression. Taken together, our results provide evidence that PI3K signaling is an important cue required for fostering development of B cells carrying a useful BCR.

subject areas

  • Animals
  • Antigens, CD19
  • B-Lymphocyte Subsets
  • Cell Differentiation
  • Cells, Cultured
  • DNA-Binding Proteins
  • Down-Regulation
  • Homeodomain Proteins
  • Ligands
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Phosphatidylinositol 3-Kinases
  • Protein Subunits
  • Receptors, Antigen, B-Cell
  • Signal Transduction
  • Up-Regulation
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Identity

PubMed Central ID

  • PMC3777394

International Standard Serial Number (ISSN)

  • 0022-1767

PubMed ID

  • 17475862
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Additional Document Info

start page

  • 6332

end page

  • 6341

volume

  • 178

issue

  • 10

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