title: Distinct spatial and molecular features of notch pathway assembly in regulatory T cells.
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 (T(regs)) 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(-/-) T(regs) 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 T(regs). 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.
authors: National Centre for Biological Sciences, Tata Institute of Fundamental Research, GKVK Campus, Bangalore 560065, India.
authors: Lakshmi R
authors: LR
authors: Perumalsamy
authors: Nimi
authors: N
authors: Marcel
authors: Sneha
authors: S
authors: Kulkarni
authors: Freddy
authors: F
authors: Radtke
authors: Apurva
authors: A
authors: Sarin
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D015153:Blotting, Western; D002135:Calcium-Binding Proteins; D002352:Carrier Proteins / Q000378:metabolism; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D002470:Cell Survival / Q000276:immunology*; D005434:Flow Cytometry; D055786:Gene Knockout Techniques; D006801:Humans; D047468:Immunoprecipitation; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D020239:Receptor Cross-Talk / Q000276:immunology; D051881:Receptor, Notch1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors
chemical_list: D002135:Calcium-Binding Proteins; D002352:Carrier Proteins; C504923:Crtc2 protein, mouse; C512925:Dlk1 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D051881:Receptor, Notch1; D015534:Trans-Activators; D014157:Transcription Factors; C525637:rictor protein, mouse; D058539:Phosphatidylinositol 3-Kinase