title: The importance of the Erk pathway in the development of linker for activation of T cells-mediated autoimmunity.
abstract: The ability of the transmembrane adaptor protein linker for activation of T cells (LAT) to regulate T cell development, activation, survival, and homeostasis depends upon phosphorylation of its multiple tyrosine residues. The mutation of tyrosine 136 on LAT abrogates its interaction with phospholipase C-γ1, causing severe ramifications on TCR-mediated signaling. Mice harboring this mutation, LATY136F mice, have significantly impaired thymocyte development; however, they rapidly develop a fatal lymphoproliferative disease marked by the uncontrolled expansion of Th2-skewed CD4(+) T cells, high levels of IgE and IgG1, and autoantibody production. In this study, we assessed the contribution of multiple signaling pathways in LATY136F disease development. The deletion of the critical signaling proteins Gads and RasGRP1 caused a further block in thymocyte development, but, over time, could not prevent CD4(+) T cell hyperproliferation. Also, restoring signaling through the NF-κB and NFAT pathways was unable to halt the development of disease. However, expression of a constitutively active Raf transgene enhanced lymphoproliferation, indicating a role for the Ras-MAPK pathway in LAT-mediated disease.
authors.affiliation: Department of Immunology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Deirdre M
authors.initials: DM
authors.lastname: Fuller
authors.forename: Minghua
authors.initials: M
authors.lastname: Zhu
authors.forename: Surapong
authors.initials: S
authors.lastname: Koonpaew
authors.forename: Mariana I
authors.initials: MI
authors.lastname: Nelson
authors.forename: Weiguo
authors.initials: W
authors.lastname: Zhang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000818:Animals; D001327:Autoimmune Diseases / Q000201:enzymology* / Q000235:genetics / Q000276:immunology*; D020662:Guanine Nucleotide Exchange Factors / Q000172:deficiency / Q000235:genetics; D008232:Lymphoproliferative Disorders / Q000201:enzymology* / Q000235:genetics / Q000276:immunology*; D020935:MAP Kinase Signaling System / Q000235:genetics / Q000276:immunology*; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010750:Phosphoproteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D011948:Receptors, Antigen, T-Cell / Q000172:deficiency / Q000235:genetics; D048490:raf Kinases / Q000096:biosynthesis / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D020662:Guanine Nucleotide Exchange Factors; C491734:Lat protein, mouse; D008565:Membrane Proteins; C498726:Mona protein, mouse; D010750:Phosphoproteins; C112278:Rasgrp1 protein, mouse; D011948:Receptors, Antigen, T-Cell; D048490:raf Kinases