Inositol 1,3,4,5-tetrakisphosphate controls proapoptotic Bim gene expression and survival in B cells

Proc Natl Acad Sci U S A. 2007 Aug 28;104(35):13978-83. doi: 10.1073/pnas.0704312104. Epub 2007 Aug 20.


The contribution of the B isoform of inositol 1,4,5-trisphosphate [Ins(1,4,5)P(3)] 3-kinase (or Itpkb) and inositol 1,3,4,5-tetrakisphosphate [Ins(1,3,4,5)P(4)], its reaction product, to B cell function and development remains unknown. Here, we show that mice deficient in Itpkb have defects in B cell survival leading to specific and intrinsic developmental alterations in the B cell lineage and antigen unresponsiveness in vivo. The decreased B cell survival is associated with a decreased phosphorylation of Erk1/2 and increased Bim gene expression. B cell survival, development, and antigen responsiveness are normalized in parallel to reduced expression of Bim in Itpkb(-/-) Bim(+/-) mice. Analysis of the signaling pathway downstream of Itpkb revealed that Ins(1,3,4,5)P(4) regulates subcellular distribution of Rasa3, a Ras GTPase-activating protein acting as an Ins(1,3,4,5)P(4) receptor. Together, our results indicate that Itpkb and Ins(1,3,4,5)P(4) mediate a survival signal in B cells via a Rasa3-Erk signaling pathway controlling proapoptotic Bim gene expression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Apoptosis Regulatory Proteins / deficiency
  • Apoptosis Regulatory Proteins / genetics*
  • B-Lymphocyte Subsets / cytology
  • B-Lymphocyte Subsets / immunology
  • B-Lymphocyte Subsets / physiology
  • B-Lymphocytes / cytology*
  • B-Lymphocytes / immunology
  • B-Lymphocytes / physiology*
  • Bcl-2-Like Protein 11
  • Bone Marrow / immunology
  • Cell Survival
  • Gene Expression Regulation
  • Immunoglobulin D / analysis
  • Immunoglobulin M / analysis
  • Inositol Phosphates / pharmacology*
  • Membrane Proteins / deficiency
  • Membrane Proteins / genetics*
  • Mice
  • Mice, Knockout
  • Phosphotransferases (Alcohol Group Acceptor) / deficiency
  • Phosphotransferases (Alcohol Group Acceptor) / genetics*
  • Proto-Oncogene Proteins / deficiency
  • Proto-Oncogene Proteins / genetics*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Spleen / immunology


  • Apoptosis Regulatory Proteins
  • Bcl-2-Like Protein 11
  • Bcl2l11 protein, mouse
  • Immunoglobulin D
  • Immunoglobulin M
  • Inositol Phosphates
  • Membrane Proteins
  • Proto-Oncogene Proteins
  • inositol-1,3,4,5-tetrakisphosphate
  • Phosphotransferases (Alcohol Group Acceptor)
  • Inositol 1,4,5-trisphosphate 3-kinase