PI3K Signaling in B Lymphocytes

Phosphoinositide-3-Kinases (PI3K) regulate numerous biological processes including cell growth, differentiation, survival, proliferation, migration and metabolism. In the immune system, impaired PI3K signaling leads to immunodeficiency whereas unrestrained signaling contributes to autoimmunity and leukemia. The Class I and III PI3Ks facilitate B cell development through defined stages, resulting in at least three distinct lineages of mature B lymphocytes. In B cells, PI3K is activated within seconds of antigen-receptor triggering. Engagement of BCR-antigen complex activates intracellular protein tyrosine kinases such as SYK, BTK and Fyn which phosphorylate the co-receptors CD19 and BCAP at the YXXM motifs. This provides binding sites for PI3Ks. CD19 is one of the main regulators of PI3K activity in B cells. CD19 has an important, but not indispensable, role in PI3K activation as it is required for sustained PI3K activation after BCR stimulation. The co-receptor complex is also composed of CD21 and CD81. CD21 binds opsonized antigenic particles and activates complement component C3, a reaction central to complement function in the immune response and sustained BCR signaling.For B cell development, the ability of CD19 to promote a thymus-dependent immune response is linked to its capacity to recruit and activate PI3K. CD19 phosphorylation activates Lyn which in turn recruits PI3K regulatory subunit (p85). Other molecules such as Vav contribute to PI3K activation in B cells by a mechanism that involves the activation of Rac1 which then binds to p85 through its RhoGAP domain. B-cell proliferation is also stimulated by IL-4 via IRS activation, LPS stimulated TLR4 activation and CD40 activated Cbl that engages p85α-associated p110Δ, thus enhancing PI3K signaling. Subsequently, PIP3 is produced at the inner leaflet of the plasma membrane which activates the Akt/PDK-1 Signaling pathway leading to the down regulation of transcription factors such as FoxO3A, thereby facilitating cell survival. Inhibitors such as PTEN and SHIP abrogate PI3K/PIP3 signaling. The PI3K signal is taken over by TAPP adaptor proteins, which have binding specificity for PIP2 and influence the process of cytoskeletal reorganization.Generation of PIP3 and PIP2 also activates DAPP1, an adaptor protein with a high affinity PIP3-binding PH domain, which generates BCR-dependent calcium flux via IP3R release of stored calcium. One of the targets regulated by calcium elevation is the transcription factor NFAT, whose nuclear translocation is facilitated through its dephosphorylation by calcineurin. PKC-β which is activated by DAG and calcium ions phosphorylates IKK, eventually resulting in the translocation of NF-κB to the nucleus. PKC also activates BIMP1/Bcl10/MALT1 that forms a strong and specific complex within the cell to synergize with the activation of NF-κB. PI3K activates the MAPK cascade via the aPKC/Raf1/MEK route where ERK regulates cell proliferation through induction of transcription factors Elk1, ATF and CREB. Thus PI3K affects the concerted regulation of several transcription factors which mediate gene transcription in B cells.