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Prot Cell    2011, Vol. 2 Issue (7) : 523-530    https://doi.org/10.1007/s13238-011-1077-3      PMID: 21822797
REVIEW
Perspectives on the role of mTORC2 in B lymphocyte development, immunity and tumorigenesis
Adam S. Lazorchak, Bing Su()
Department of Immunobiology and the Vascular Biology and Therapeutic Program, Yale School of Medicine, New Haven, CT 06519, USA
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Abstract

Mammalian target of rapamycin complex 2 (mTORC2) is a key downstream mediator of phosphoinositol-3-kinase (PI3K) dependent growth factor signaling. In lymphocytes, mTORC2 has emerged as an important regulator of cell development, homeostasis and immune responses. However, our current understanding of mTORC2 functions and the molecular mechanisms regulating mTORC2 signaling in B and T cells are still largely incomplete. Recent studies have begun to shed light on this important pathway. We have previously reported that mTORC2 mediates growth factor dependent phosphorylation of Akt and facilitates Akt dependent phosphorylation and inactivation of transcription factors FoxO1 and FoxO3a. We have recently explored the functions of mTORC2 in B cells and show that mTORC2 plays a key role in regulating survival and immunoglobulin (Ig) gene recombination of bone marrow B cells through an Akt2-FoxO1 dependent mechanism. Ig recombination is suppressed in proliferating B cells to ensure that DNA double strand breaks are not generated in actively dividing cells. Our results raise the possibility that genetic or pharmacologic inhibition of mTORC2 may promote B cell tumor development as a result of inefficient suppression of Ig recombination in dividing B cells. We also propose a novel strategy to treat cancers based on our recent discovery that mTORC2 regulates Akt protein stability.
Keywords mTOR      lymphocyte      B cell      cancer      mTORC2      FoxO      Akt      Sin1     
Corresponding Author(s): Su Bing,Email:bing.su@yale.edu   
Issue Date: 01 July 2011
 Cite this article:   
Adam S. Lazorchak,Bing Su. Perspectives on the role of mTORC2 in B lymphocyte development, immunity and tumorigenesis[J]. Prot Cell, 2011, 2(7): 523-530.
 URL:  
https://academic.hep.com.cn/pac/EN/10.1007/s13238-011-1077-3
https://academic.hep.com.cn/pac/EN/Y2011/V2/I7/523
Fig.1  The role of mTORC2 in B cell development in the bone marrow.
Progenitor B (pro-B) cells that differentiate from bone marrow common lymphoid progenitors are dependent on IL-7 for growth and cell viability. Pro-B cells that produce a functional IgH allele by somatic recombination will express a surface pre-BCR and differentiate into large precursor B (pre-B) cells. Mammalian TORC2 mediates pre-BCR signals to suppress RAG expression which inhibits further IgH gene recombination and suppresses IL-7 receptor expression to limit the IL-7 dependent growth, proliferation, and survival of pre-B cells. Down regulation of the pre-BCR expression facilitates the transition to the small pre-B cell stage and the initiation of IgL recombination. Production of a functional IgL allele results in expression of the BCR on immature B cells. Immature B cells that express a self reactive BCR may attempt additional IgL rearrangements to produce a new, potentially non-self reactive BCR. Expression of a non-self reactive BCR inhibits IgL recombination through a mechanism which is, in part, mediated by mTORC2 dependent suppression of RAG expression. Surface BCR expression is required for further B cell maturation and survival in the spleen.
Fig.1  The role of mTORC2 in B cell development in the bone marrow.
Progenitor B (pro-B) cells that differentiate from bone marrow common lymphoid progenitors are dependent on IL-7 for growth and cell viability. Pro-B cells that produce a functional IgH allele by somatic recombination will express a surface pre-BCR and differentiate into large precursor B (pre-B) cells. Mammalian TORC2 mediates pre-BCR signals to suppress RAG expression which inhibits further IgH gene recombination and suppresses IL-7 receptor expression to limit the IL-7 dependent growth, proliferation, and survival of pre-B cells. Down regulation of the pre-BCR expression facilitates the transition to the small pre-B cell stage and the initiation of IgL recombination. Production of a functional IgL allele results in expression of the BCR on immature B cells. Immature B cells that express a self reactive BCR may attempt additional IgL rearrangements to produce a new, potentially non-self reactive BCR. Expression of a non-self reactive BCR inhibits IgL recombination through a mechanism which is, in part, mediated by mTORC2 dependent suppression of RAG expression. Surface BCR expression is required for further B cell maturation and survival in the spleen.
Fig.2  A model illustrating the growth factor independent [1] and growth factor dependent [2] functions of mTORC2 in pre-B cells.
[1] mTORC2 promotes the stability of maturation of newly synthesized Akt and classical (c)PKC polypeptides. In this example, we show that mTORC2, associated with ribosomes in a growth factor independent manner, phosphorylates the TM site of the Akt polypeptide. TM phosphorylation stabilizes the nascent Akt polypeptide and facilitates the maturation of the properly folded Akt protein. The chaperone protein Hsp90 may facilitate the proper maturation of Akt or cPKC and stabilize these proteins if TM phosphorylation is inhibited. [2] Expression of a functional pre-BCR signals to PI3K. PDK1 and mTORC2 then mediate the PI3K signals to phosphorylate Akt at the T-loop and HM sites, respectively. Activated Akt2 then phosphorylates FoxO1 in the nucleus resulting in the down regulation of FoxO1 transcriptional activity and reduced and gene expression. Loss of mTORC2 function in developing B cells blocks Akt2 HM site phosphorylation and prevents the full activation of Akt2 resulting in insufficient inhibition of FoxO1. This leads to increased and gene expression resulting in increased IL-7 dependent survival and increased recombinase activity, respectively, in developing B cells
Fig.2  A model illustrating the growth factor independent [1] and growth factor dependent [2] functions of mTORC2 in pre-B cells.
[1] mTORC2 promotes the stability of maturation of newly synthesized Akt and classical (c)PKC polypeptides. In this example, we show that mTORC2, associated with ribosomes in a growth factor independent manner, phosphorylates the TM site of the Akt polypeptide. TM phosphorylation stabilizes the nascent Akt polypeptide and facilitates the maturation of the properly folded Akt protein. The chaperone protein Hsp90 may facilitate the proper maturation of Akt or cPKC and stabilize these proteins if TM phosphorylation is inhibited. [2] Expression of a functional pre-BCR signals to PI3K. PDK1 and mTORC2 then mediate the PI3K signals to phosphorylate Akt at the T-loop and HM sites, respectively. Activated Akt2 then phosphorylates FoxO1 in the nucleus resulting in the down regulation of FoxO1 transcriptional activity and reduced and gene expression. Loss of mTORC2 function in developing B cells blocks Akt2 HM site phosphorylation and prevents the full activation of Akt2 resulting in insufficient inhibition of FoxO1. This leads to increased and gene expression resulting in increased IL-7 dependent survival and increased recombinase activity, respectively, in developing B cells
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