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Sci. Signal., 24 July 2012
Vol. 5, Issue 234, p. ra53
[DOI: 10.1126/scisignal.2002859]

RESEARCH ARTICLES

Distinct Spatial and Molecular Features of Notch Pathway Assembly in Regulatory T Cells

Lakshmi R. Perumalsamy1, Nimi Marcel1,2, Sneha Kulkarni1, Freddy Radtke3, and Apurva Sarin1*

1 National Centre for Biological Sciences, Tata Institute of Fundamental Research, GKVK Campus, Bangalore 560065, India.
2 Manipal University, Manipal, Karnataka 576104, India.
3 Ecole Polytechnique Fédérale de Lausanne, Swiss Institute for Experimental Cancer Research, Station 19, 1015 Lausanne, Switzerland.

Abstract: Variations in the spatial localization of signaling components and crosstalk among signaling cascades are mechanisms through which diversity in signaling networks is generated. The receptor Notch provides an example of regulation by spatial localization: In the canonical Notch signaling pathway, Notch is cleaved to produce the Notch intracellular domain (NICD, also known as NIC), which translocates to the nucleus to regulate gene expression. We describe a T cell receptor–dependent, non-nuclear distribution and function of the processed receptor Notch, which was associated with the improved survival of regulatory T cells (Tregs) in vitro and in vivo and was compromised by T cell–specific deletion of Notch1. Unlike a nuclear-restricted mutant of NICD, mutant NICD that underwent nuclear export or was targeted to the plasma membrane protected Notch1–/– Tregs from apoptosis induced by nutrient deprivation and oxidative stress. Notch signaling integrated with phosphatidylinositol 3-kinase signaling and mammalian target of rapamycin complex 2 (mTORC2) for this cell survival function. Biochemical and imaging approaches revealed a membrane-proximal complex containing NICD and the mTORC2 component Rictor, and this complex was stabilized by specific interactions with the Notch ligand Delta-like–1 and mediated the survival of Tregs. Together, our evidence for the spatial control of Notch and the crosstalk of Notch signaling with other pathways reveals coupling between the localization of Notch and diverse intracellular signaling pathways.

* To whom correspondence should be addressed. E-mail: sarina{at}ncbs.res.in

Citation: L. R. Perumalsamy, N. Marcel, S. Kulkarni, F. Radtke, A. Sarin, Distinct Spatial and Molecular Features of Notch Pathway Assembly in Regulatory T Cells. Sci. Signal. 5, ra53 (2012).

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THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Noncanonical NOTCH Signaling Limits Self-Renewal of Human Epithelial and Induced Pluripotent Stem Cells through ROCK Activation.
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Notch and the Survival of Regulatory T Cells: Location Is Everything!.
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