Distinct signaling mechanisms activate the target of rapamycin in response to different B‐cell stimuli

Donahue, Amber C.; Fruman, David A.

doi:10.1002/eji.200737281

Cited by 72 publications

(77 citation statements)

References 70 publications

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“…MZ B cells show higher activation of PI3K signaling pathways than FO B cells. 49 Consistent with roles of PIP3 and Akt in preferentially promoting the MZ fate, decreasing the PIP3 phosphatase PTEN increased MZ B-cell numbers, whereas Akt was vital for generating MZ B cells. 15,32 These results suggest that PIP3 levels guide fate decisions of mature B cells in part through mTORC2 regulation of Akt.…”

Section: Discussionmentioning

confidence: 70%

Requirement for Rictor in homeostasis and function of mature B lymphoid cells

Lee

Heffington

Jellusova

et al. 2013

Blood

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• Maturation, homeostasis, and function of peripheral B lymphoid cells require Rictor, an essential mTOR complex 2 component.• Rictor regulates survival of B cells and their balance of proapoptotic vs antiapoptotic gene expression.The mammalian target of rapamycin (mTOR), an essential serine/threonine kinase, functions in biochemically distinct multiprotein complexes, but little is known about roles of the complexes in B cells. The acutely rapamycin-sensitive mTOR complex 1 (mTORC1) is defined by a core subunit Raptor, whereas mTORC2 lacks Raptor and, instead, has Rictor and SIN1 as distinct essential components. We now show that homeostasis and function of B cells require Rictor. Conditional deletion of Rictor before lymphoid specification impaired generation of mature follicular, marginal zone, and B1a B lymphocytes. Induced inactivation in adult mice caused cell-autonomous defects in B lymphoid homeostasis and antibody responses in vivo, along with affecting plasma cells in bone marrow. Survival of B lymphocytes depended on Rictor, which was vital for normal induction of prosurvival genes, suppression of proapoptotic genes, nuclear factor kB induction after B-cell receptor stimulation, and B-cell activating factor-induced nuclear factor kB2/p52 generation. Collectively, the findings provide evidence that mTOR signaling affects survival and proliferation of mature B lymphocytes, and establish Rictor as an important signal relay in B-cell homeostasis, fate, and functions. (Blood. 2013;122(14):2369-2379

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Section: Discussionmentioning

confidence: 70%

Requirement for Rictor in homeostasis and function of mature B lymphoid cells

Lee

Heffington

Jellusova

et al. 2013

Blood

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“…Some phenotypes in the mTOR-compromised mice mirror effects seen in rapamycin-treated cells, which are also smaller and less numerous than their nontreated counterparts. 39,40 In addition, rapamycin has been shown to increase Akt phosphorylation in response to LPS 41 and to decrease IgM production to formalinized Staphylococcus. 42 Reduced mTOR protein levels did not profoundly affect thymic development of T cells; however, spleens of the mTORcompromised mice exhibited several altered phenotypes, including reduced T-cell activation and differentiation.…”

Section: Discussionmentioning

confidence: 99%

Constitutive reductions in mTOR alter cell size, immune cell development, and antibody production

Zhang

Readinger

Dubois

et al. 2011

Blood

110

137

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Mammalian TOR (mTOR) regulates cell growth, proliferation, and migration. Because mTOR knock-outs are embryonic lethal, we generated a viable hypomorphic mouse by neo-insertion that partially disrupts mTOR transcription and creates a potential physiologic model of mTORC1/ TORC2 inhibition. Homozygous knock-in mice exhibited reductions in body, organ, and cell size. Although reductions in most organ sizes were proportional to decreased body weight, spleens were disproportionately smaller. Decreases in the total number of T cells, particularly memory cells, and reduced responses to chemokines suggested alterations in T-cell homing/homeostasis. T-cell receptor-stimulated T cells proliferated less, produced lower cytokine levels, and expressed FoxP3. Decreased neutrophil numbers were also observed in the spleen, despite normal development and migration in the bone marrow. However, B-cell effects were most pronounced, with a partial block in B-cell development in the bone marrow, altered splenic populations, and decreases in proliferation, antibody production, and migration to chemokines. Moreover, increased AKT Ser473 phosphorylation was observed in activated B cells, reminiscent of cancers treated with rapamycin, and was reduced by a DNA-pk inhibitor. Thus, mTOR is required for the maturation and differentiation of multiple immune cell lineages. These mice provide a novel platform for studying the consequences of constitutively reduced mTORC1/TORC2 activity. IntroductionThe mammalian target of rapamycin (mTOR) is part of a conserved pathway regulating fundamental physiologic functions, including nutrient sensing and metabolism, and cell growth, proliferation, and migration. mTOR forms 2 protein complexes: one with RAPTOR, mLST8(G␤L), and PRAS40 to form TOR complex 1 (mTORC1) involved in phosphorylating S6K and 4EBP1, 1,2 and a second with RICTOR, mLST8(G␤L), SIN1, and PROTOR to form TOR complex 2 (mTORC2), which phosphorylates AKT on Ser473. [2][3][4] In yeast, TOR controls cell proliferation and size. 5,6 In Drosophila, inactivation of dTOR results in lethality and reduced embryo size. 7,8 Genetically targeting the kinase domain of murine mTOR for inactivation results in embryonic lethality, 9-11 although deletions in the C terminal portion yield mice that are normal and fertile. 11 ENU-mutagenesis screens uncovered an additional embryonic lethal mutation of mTOR, resulting in flat-top embryos lacking telencephalons resulting from limited neuroectodermal cell proliferation. 10,12 Knockouts of Raptor or Sin1 13 result in early embryonic lethality, whereas those of Rictor and mLST8(G␤L) lead to late embryonic lethality and defective vascular development. mTOR signaling/function has been deduced from studies with rapamycin, which associates with FKBP12, 14 and together binds mTOR to destabilize mTORC1. Although originally thought to affect only mTORC1, long-term treatment with rapamycin can also affect mTORC2. 15 Rapamycin and numerous rapalogs are potent immunosuppressants used in cancer chemotherapy and bone marro...

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“…LPS-mediated B cell proliferation is defective in mice lacking the p85a regulatory subunit of PI3K (42), and mTOR inhibition blocks both BCR and LPS-mediated proliferation and S6 kinase activation (43). In addition, the PI3K/Akt pathway has also been shown to play a critical role in CpG-mediated human B cell activation (44).…”

Section: Discussionmentioning

confidence: 99%

Type I IFN Receptor and the B Cell Antigen Receptor Regulate TLR7 Responses via Distinct Molecular Mechanisms

Poovassery

Bishop

2012

The Journal of Immunology

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Toll-like receptor 7 (TLR7) signals to B cells are critically involved in the innate immune response to microbes, as well as pathogenesis of autoimmune diseases, but the molecular mechanisms that normally regulate these responses are incompletely understood. We previously reported that repeated stimulation through TLR7 induces a state of hyporesponsiveness (TLR tolerance) in both human and mouse B cells, characterized by marked inhibition of particular signaling pathways. BCR signals prevent and overcome TLR7 tolerance. Because optimal responses to TLR7 in B cells require type I IFN, we investigated whether BCR-mediated effects on TLR7 tolerance are mediated by type I IFN receptor (IFNAR) signals. Surprisingly, although BCR-mediated reversal of TLR7 tolerance was IFNAR independent, IFNAR signals alone also blocked TLR7 tolerance, despite enhancing TLR7 expression. Both BCR and IFNAR signals restored the phosphorylation of the transcriptional regulator c-Jun, but only BCR signals blocked the tolerance-mediated inhibition of JNK. Both BCR and IFNAR-mediated regulation was dependent on activation of the PI3K/Akt/mammalian target of rapamycin signaling pathway, indicating a central role for this axis in integrating TLR7, BCR, and IFNAR signals in B cells. These new findings reveal distinct and overlapping signaling mechanisms used by BCR and IFNAR in the regulation of TLR7 tolerance and activation.

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Distinct signaling mechanisms activate the target of rapamycin in response to different B‐cell stimuli

Cited by 72 publications

References 70 publications

Requirement for Rictor in homeostasis and function of mature B lymphoid cells

Requirement for Rictor in homeostasis and function of mature B lymphoid cells

Constitutive reductions in mTOR alter cell size, immune cell development, and antibody production

Type I IFN Receptor and the B Cell Antigen Receptor Regulate TLR7 Responses via Distinct Molecular Mechanisms

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