Constitutive Akt1 signals attenuate B‐cell receptor signaling and proliferation, but enhance B‐cell migration and effector function

Abstract

Ligation of the BCR induces a complex signaling network that involves activation ofAkt, a family of serine/threonine protein kinases associated with B-cell development, proliferation, and tumor formation. Here, we analyzed the effect of enhanced Akt1 signals on B-cell maturation and function. Unexpectedly, we found that peripheral B cells overexpressing Akt1 were less responsive to BCR stimuli. This correlated with a decrease in Ca 2+ -mobilization and proliferation, in an impaired activation of Erk1/2 and mammalian target of rapamycin (mTOR) kinases and poor mobilization of NFATc1 and NF-κB/p65 factors. In contrast, activation of STAT5 and migration of B cells toward the chemokine SDF1α was found to be enhanced. Akt1 Tg mice showed an altered maturation of peritoneal and splenic B1 B cells and an enhanced production of IgG1 and IgG3 upon immunization with the T-cell independent Ag TNP-Ficoll. Furthermore, mice homozygous for Tg Akt1 showed a severe block in the maturation of B-cell precursors in BM and a strong enrichment of plasma cells in spleen. Altogether, our data reveal that enhanced Akt1 signals modify BCR signaling strength and, thereby, B-cell development and effector function.Keywords: B cell r NFAT r PKB/Akt r SDF1α r STAT5 IntroductionIn the BM B-cell progenitors develop through defined stages of differentiation to immature B cells giving rise to follicular B2 (FO) B cells, marginal zone (MZ), and B1 B cells. These processes are controlled by the signal intensity arising from the pre-BCR or mature BCR, which activate similar sets of signaling molecules. The most proximal signaling events upon BCR ligation include Correspondence: Prof. Ursula H. Bommhardt e-mail: ursula.bommhardt@med.ovgu.de activation of the protein tyrosine kinases Lyn and Syk. A prominent substrate of Syk is the adaptor protein SLP65/BLNK, which recruits Bruton's tyrosine kinase, phospholipase Cγ2, and further signal proteins into supramolecular complexes that trigger the activation of multiple signaling pathways. Activated phospholipase Cγ2 cleaves the membrane lipid phosphatidylinositol-4, 5-bisphosphate (PIP2) to generate diacylglycerol and inositol-1,4,5-trisphosphate (IP3), two second messengers affecting the * These authors contributed equally to this work. Eur. J. Immunol. 2012. 42: 3381-3393 activation of PKC family members, MAPK activation, and the release of Ca 2+ from intracellular stores, which finally leads to influx of extracellular Ca 2+ . Elevated intracellular Ca 2+ -levels induce the activity of serine/threonine-specific phosphatase calcineurin and, in turn, a set of Ca 2+ -regulated transcription factors, in particular of NFAT and NF-κB factors that control various gene expression programs [1].An important signaling cascade induced after BCR engagement encompasses the lipid kinase family of class I PI3Ks [2][3][4]. Mature peripheral B cells lacking a BCR could be rescued from apoptosis by the ectopic expression of a constitutively active catalytic subunit of PI3K, indicating that PI3K signals support the surv...

Distinct roles of Akt1 in regulating proliferation, migration and invasion in HepG2 and HCT 116 cells

“…Consistent with our observations, Pierau et al (7) demonstrated that constitutive Akt1 signals attenuate B-cell receptor signaling and proliferation, but enhance B-cell migration and effector function. Moreover, our results also demonstrated that overexpression of Akt1 promoted the cell migration and invasion of human liver cancer HepG2 cells; however, it attenuated the cell migration and invasion of human colorectal carcinoma HCT 116 cells.…”

“…However, the role of Akt1 in cell proliferation remains controversial. For instance, a recent article indicated that constitutive Akt1 signals attenuate B-cell receptor signaling and proliferation (7). Therefore, it is essential to investigate whether ectopic expression of Akt1 promotes cell proliferation or not in other cell types, including hepatocellular carcinoma (HCC) and colorectal cancer cells.…”

Glioma‐derived macrophage migration inhibitory factor (MIF) promotes mast cell recruitment in a STAT5‐dependent manner

“…Together, these findings indicate that gliomas recruit MCs by secreting MIF, which induces the migration of these cells through mechanisms involving signaling by STAT5. This conclusion is in agreement with observations that STAT5 enhances migration by other immune cells, e.g ., B‐cells (Pierau et al., 2012).…”

Cryptic collagen IV promotes cell migration and adhesion in myeloid leukemia

“…Activation of AKT has been shown to promote migration of Th1 lymphocytes via CD152/CCL4/CCR5-mediated PI3K activation [10]. Further, constitutive activation of AKT during B cell maturation lead to increased STAT5 activation and cell migration to the chemokine SDF1a [11]. Furthermore, hematopoietic stem cells (HSCs) are highly sensitive to AKT/mTOR signaling and importantly; increased activation of AKT in HSCs induces AML at the expense of HSC pool [12].…”