Article

The PI3K isoforms p110{alpha} and p110{delta} are essential for Pre-B cell receptor signaling and B cell development

1Laboratory of Lymphocyte Signalling and Development, Babraham Institute, Cambridge CB22 3AT, UK.
Science Signaling (Impact Factor: 7.65). 08/2010; 3(134):ra60. DOI: 10.1126/scisignal.2001104
Source: PubMed

ABSTRACT B cell development is controlled by a series of checkpoints that ensure that the immunoglobulin (Ig)-encoding genes produce a functional B cell receptor (BCR) and antibodies. As part of this process, recombination-activating gene (Rag) proteins regulate the in-frame assembly of the Ig-encoding genes. The BCR consists of Ig proteins in complex with the immunoreceptor tyrosine-based activation motif (ITAM)-containing Igalpha and Igbeta chains. Whereas the activation of the tyrosine kinases Src and Syk is essential for BCR signaling, the pathways that act downstream of these kinases are incompletely defined. Previous work has revealed a key role for the p110delta isoform of phosphatidylinositol 3-kinase (PI3K) in agonist-induced BCR signaling; however, early B cell development and mature B cell survival, which depend on agonist-independent or "tonic" BCR signaling, are not substantially affected by a deficiency in p110delta. Here, we show that p110alpha, but not p110beta, compensated in the absence of p110delta to promote early B cell development in the bone marrow and B cell survival in the spleen. In the absence of both p110alpha and p110delta activities, pre-BCR signaling failed to suppress the production of Rag proteins and to promote developmental progression of B cell progenitors. Unlike p110delta, however, p110alpha did not contribute to agonist-induced BCR signaling. These studies indicate that either p110alpha or p110delta can mediate tonic signaling from the BCR, but only p110delta can contribute to antigen-dependent activation of B cells.

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    • "Activation of downstream pathways is initiated by the recruitment of effector molecules such as PDK1, Akt, Btk, and PLCg2, which bear pleckstrin homology (PH) domains that directly bind PtdIns(3,4,5)P 3 (Baracho et al., 2011). p110d-deficient B cells exhibit impaired BAFF-induced survival (Henley et al., 2008), and combined inactivation of p110a/d results in failed B cell generation or accumulation (Ramadani et al., 2010). Using Akt phosphorylation as a surrogate readout, investigators have observed that BAFF induces PI3K activity with both rapid and delayed kinetics (Otipoby et al., 2008; Patke et al., 2006). "
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