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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    • "In addition to the productive rearrangements required to produce the pre-BCR, pre-B cell development in the mouse also requires signaling through the IL-7R, as mice lacking signaling components of the IL-7 receptor have few pre-B cells (Peschon et al. 1994; Clark et al. 2014). Similarly, absence of the signaling cascade components that follow IL-7R activation such as STAT5 (A and B) (Goetz et al. 2004; Yao et al. 2006), cyclin D3 (Cooper et al. 2006), and phosphoinositide 3-kinase (PI3K) (Ramadani et al. 2010; Fruman et al. 1999; Suzuki et al. 1999; Clayton et al. 2002; Jou et al. 2002; Okkenhaug et al. 2002) greatly attenuate the proliferation and survival of pre-B cells. Interestingly, mutation in ATP11c, a P4 ATPases (flippase) that is required for IL-7 signaling, results in a progressive loss of pro-and pre-B cells (Clark 2011; Pang and Nutt 2011; Siggs et al. 2011; Yabas et al. 2011). "
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    Current topics in microbiology and immunology 05/2014; 381. DOI:10.1007/82_2014_377 · 3.47 Impact Factor
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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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    Cell Reports 11/2013; 5(4). DOI:10.1016/j.celrep.2013.10.022 · 8.36 Impact Factor
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    • "p110β also appears to be dispensable for both B-cell development and activation [79]. Although deficiency in p110α does not affect B-cell development or BCR signaling, combined deletion of p110α and p110δ leads to a nearly complete block in B-cell development [79]. This result suggests that p110α may make an important contribution to tonic pre- BCR and BCR signaling, but is less important for signaling induced by the acute BCR clustering induced by Ag binding. "
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