title: DLGH1 is a negative regulator of T-lymphocyte proliferation.
abstract: Discs large homolog 1 (DLGH1), a founding member of the membrane-associated guanylate kinase family of proteins containing PostSynaptic Density-95/Discs large/Zona Occludens-1 domains, is an ortholog of the Drosophila tumor suppressor gene Discs large. In the mammalian embryo, DLGH1 is essential for normal urogenital morphogenesis and the development of skeletal and epithelial structures. Recent reports also indicate that DLGH1 may be a critical mediator of signals triggered by the antigen receptor complex in T lymphocytes by functioning as a scaffold coordinating the activities of T-cell receptor (TCR) signaling proteins at the immune synapse. However, it remains unclear if DLGH1 functions to enhance or attenuate signals emanating from the TCR. Here, we used Dlgh1 gene-targeted mice to determine the requirement for DLGH1 in T-cell development and activation. Strikingly, while all major subsets of T cells appear to undergo normal thymic development in the absence of DLGH1, peripheral lymph node Dlgh1(-/-) T cells show a hyper-proliferative response to TCR-induced stimulation. These data indicate that, consistent with the known function of Discs large proteins as tumor suppressors and attenuators of cell division, in T lymphocytes, DLGH1 functions as a negative regulator of TCR-induced proliferative responses.
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO 63110, USA. swat@wustl.edu.
authors.forename: Linda M
authors.initials: LM
authors.lastname: Stephenson
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Sammut
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Graham
authors.forename: Joaquim
authors.initials: J
authors.lastname: Chan-Wang
authors.forename: Karry L
authors.initials: KL
authors.lastname: Brim
authors.forename: Alan S
authors.initials: AS
authors.lastname: Huett
authors.forename: Ana V
authors.initials: AV
authors.lastname: Miletic
authors.forename: Tracie
authors.initials: T
authors.lastname: Kloeppel
authors.forename: Aimee
authors.initials: A
authors.lastname: Landry
authors.forename: Ramnik
authors.initials: R
authors.lastname: Xavier
authors.forename: Wojciech
authors.initials: W
authors.lastname: Swat
mesh_terms: D000199:Actins / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000378:metabolism*; D000818:Animals; D016764:Cell Polarity; D049109:Cell Proliferation; D016207:Cytokines / Q000096:biosynthesis; D003599:Cytoskeleton / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000172:deficiency; D000074288:Discs Large Homolog 1 Protein; D005333:Fetus / Q000166:cytology; D005786:Gene Expression Regulation; D051528:Guanylate Kinases; D008099:Liver / Q000166:cytology; D008565:Membrane Proteins / Q000172:deficiency / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D021381:Protein Transport; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D016196:S Phase; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology*
chemical_list: D000199:Actins; D048868:Adaptor Proteins, Signal Transducing; D016207:Cytokines; D004268:DNA-Binding Proteins; D000074288:Discs Large Homolog 1 Protein; C000614189:Dlg1 protein, mouse; D008565:Membrane Proteins; D016271:Proto-Oncogene Proteins c-myc; C499308:Rag2 protein, mouse; D011948:Receptors, Antigen, T-Cell; D051528:Guanylate Kinases