title: The Notch regulator Numb links the Notch and TCR signaling pathways.
abstract: Both the Notch and TCR signaling pathways play an important role in T cell development, but the links between these signaling pathways are largely unexplored. The adapter protein Numb is a well-characterized inhibitor of Notch and also contains a phosphotyrosine binding domain, suggesting that Numb could provide a link between these pathways. We explored this possibility by investigating the physical interactions among Notch, Numb, and the TCR signaling apparatus and by examining the consequences of a Numb mutation on T cell development. We found that Notch and Numb cocluster with the TCR at the APC contact during Ag-driven T cell-APC interactions in both immature and mature T cells. Furthermore, Numb coimmunoprecipitates with components of the TCR signaling apparatus. Despite this association, T cell development and T cell activation occur normally in the absence of Numb, perhaps due to the expression of the related protein, Numblike. Together our data suggest that Notch and TCR signals may be integrated at the cell membrane, and that Numb may be an important adapter in this process.
authors.affiliation: Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720, USA. aanderson@rics.bwh.harvard.edu
authors.forename: Ana C
authors.initials: AC
authors.lastname: Anderson
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Kitchens
authors.forename: Shiao Wei
authors.initials: SW
authors.lastname: Chan
authors.forename: Charles
authors.initials: C
authors.lastname: St Hill
authors.forename: Yuh Nung
authors.initials: YN
authors.lastname: Jan
authors.forename: Weimin
authors.initials: W
authors.lastname: Zhong
authors.forename: Ellen A
authors.initials: EA
authors.lastname: Robey
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D017353:Gene Deletion; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051881:Receptor, Notch1; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D011956:Receptors, Cell Surface / Q000378:metabolism* / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D013950:Thymus Gland / Q000166:cytology / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism* / Q000502:physiology
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C497762:Notch1 protein, mouse; C106293:Numb protein, mouse; C106292:Numbl protein, mouse; D051881:Receptor, Notch1; D011948:Receptors, Antigen, T-Cell; D011956:Receptors, Cell Surface; D014157:Transcription Factors