A LAT mutation that inhibits T cell development yet induces lymphoproliferation.
Mice homozygous for a single tyrosine mutation in LAT (linker for activation of T cells) exhibited an early block in T cell maturation but later developed a polyclonal lymphoproliferative disorder and signs of autoimmune disease. T cell antigen receptor (TCR)-induced activation of phospholipase C-gamma1 (PLC-gamma1) and of nuclear factor of activated T cells, calcium influx, interleukin-2 production, and cell death were reduced or abrogated in T cells from LAT mutant mice. In contrast, TCR-induced Erk activation was intact. These results identify a critical role for integrated PLC-gamma1 and Ras-Erk signaling through LAT in T cell development and homeostasis.
Sommers
Connie L
CL
Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Park
Cheung-Seog
CS
Lee
Jan
J
Feng
Chiguang
C
Fuller
Claudette L
CL
Grinberg
Alexander
A
Hildebrand
Jay A
JA
Lacaná
Emanuela
E
Menon
Rashmi K
RK
Shores
Elizabeth W
EW
Samelson
Lawrence E
LE
Love
Paul E
PE
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000974:Antibodies, Antinuclear / Q000097:blood; D001327:Autoimmune Diseases / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000502:physiology; D018956:CD5 Antigens / Q000032:analysis; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D002352:Carrier Proteins / Q000235:genetics* / Q000502:physiology*; D002455:Cell Division; D007376:Interleukin-2 / Q000096:biosynthesis; D007527:Isoenzymes / Q000378:metabolism*; D008213:Lymphocyte Activation; D008232:Lymphoproliferative Disorders / Q000209:etiology* / Q000276:immunology / Q000473:pathology; D020935:MAP Kinase Signaling System; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010641:Phenotype; D051966:Phospholipase C gamma; D010750:Phosphoproteins / Q000235:genetics* / Q000502:physiology*; D010766:Phosphorylation; D017354:Point Mutation; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000502:physiology; D013601:T-Lymphocytes / Q000276:immunology* / Q000502:physiology; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology / Q000473:pathology; D014157:Transcription Factors / Q000378:metabolism; D010738:Type C Phospholipases / Q000378:metabolism*; D018631:ras Proteins / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D000974:Antibodies, Antinuclear; D018956:CD5 Antigens; D002352:Carrier Proteins; D007376:Interleukin-2; D007527:Isoenzymes; C491734:Lat protein, mouse; D008565:Membrane Proteins; D010750:Phosphoproteins; D011948:Receptors, Antigen, T-Cell; D014157:Transcription Factors; D020928:Mitogen-Activated Protein Kinases; D010738:Type C Phospholipases; D051966:Phospholipase C gamma; D018631:ras Proteins; D002118:Calcium