Vital roles of mTOR complex 2 in Notch-driven thymocyte differentiation and leukemia

Lee, Keunwook; Nam, Ki Taek; Cho, Sung Hoon; Gudapati, Prathyusha; Hwang, Young Sil; Park, Do‐Sim; Potter, Ross M.; Chen, Jin; Volanakis, Emmanuel J.; Boothby, Mark

doi:10.1084/jem.20111470

Cited by 112 publications

(111 citation statements)

References 75 publications

(122 reference statements)

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“…For example, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a disease caused by mutations in NOTCH3 (Joutel et al 1996), is associated with mitochondrial impairment (Dotti et al 2004). On the other hand, GOF mutations of Notch1 are implicated in over half of human T-cell acute lymphoblastic leukemia (T-ALL) (Weng et al 2004), in which a pathogenic role of mTORC2 has been proposed, although how N impinges on mTORC2 in this setting is unknown (Lee et al 2012). Mammalian N has been shown to act through AKT and mitochondria to promote T-cell survival (Perumalsamy et al 2010), although the mechanism is distinct from the one uncovered here.…”

Section: Resultsmentioning

confidence: 99%

Roles of PINK1, mTORC2, and mitochondria in preserving brain tumor-forming stem cells in a noncanonical Notch signaling pathway

Lee

Song

et al. 2013

Genes Dev.

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The self-renewal versus differentiation choice of Drosophila and mammalian neural stem cells (NSCs) requires Notch (N) signaling. How N regulates NSC behavior is not well understood. Here we show that canonical N signaling cooperates with a noncanonical N signaling pathway to mediate N-directed NSC regulation. In the noncanonical pathway, N interacts with PTEN-induced kinase 1 (PINK1) to influence mitochondrial function, activating mechanistic target of rapamycin complex 2 (mTORC2)/AKT signaling. Importantly, attenuating noncanonical N signaling preferentially impaired the maintenance of Drosophila and human cancer stem cell-like tumor-forming cells. Our results emphasize the importance of mitochondria to N and NSC biology, with important implications for diseases associated with aberrant N signaling.

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Section: Resultsmentioning

confidence: 99%

Roles of PINK1, mTORC2, and mitochondria in preserving brain tumor-forming stem cells in a noncanonical Notch signaling pathway

Lee

Song

et al. 2013

Genes Dev.

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“…In T lymphoid cells and fibroblasts, mTORC2 has no apparent impact on cell survival and only a modest effect on proliferation. 25,26,29 To investigate survival and differentiation signals initiated by the BCR and PI3K, we analyzed a loss-of-function model for mTORC2. Specifically, we used a conditional Rictor allele that can be disrupted after stage-specific expression or chemical activation of Cre recombinase.…”

Section: Introductionmentioning

confidence: 99%

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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“…One exception is that mTOR regulation of Tlymphocyte development requires both mTORC1 and mTORC2, because deletion of either Raptor (data not shown) or Rictor impairs thymocyte differentiation. 16,17 Interestingly, while mTOR deficiency causes a reduction in myeloid cells, these cells are increased in Raptor -/-or Raptor -/-; Rictor -/-mice. 14 Thus, mTOR may act in a way that is not strictly dependent on mTORC1 and mTORC2 in myeloid cells.…”

mentioning

confidence: 99%

Mouse gene targeting reveals an essential role of mTOR in hematopoietic stem cell engraftment and hematopoiesis

Guo¹,

Zhang²,

Grogg³

et al. 2013

Haematologica

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Vital roles of mTOR complex 2 in Notch-driven thymocyte differentiation and leukemia

Abstract: Rictor is essential in Notch-driven T-ALL pathogenesis.

Cited by 112 publications

References 75 publications

Roles of PINK1, mTORC2, and mitochondria in preserving brain tumor-forming stem cells in a noncanonical Notch signaling pathway

Roles of PINK1, mTORC2, and mitochondria in preserving brain tumor-forming stem cells in a noncanonical Notch signaling pathway

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

Mouse gene targeting reveals an essential role of mTOR in hematopoietic stem cell engraftment and hematopoiesis

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