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

par Marechal, Yoann ;Pesesse, Xavier ;Jia, Yonghui;Pouillon, Valérie ;Perez-Morga, David ;Daniel, Julien ;Izui, Shozo;Cullen, Peter J;Leo, Oberdan ;Luo, Hongbo R;Erneux, Christophe ;Schurmans, Stéphane
Référence Proceedings of the National Academy of Sciences of the United States of America, 104, 35, page (13978-13983)
Publication Publié, 2007-08

Article révisé par les pairs

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Résumé :

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.