title: A phospholipase C-γ1-independent, RasGRP1-ERK-dependent pathway drives lymphoproliferative disease in linker for activation of T cells-Y136F mutant mice.
abstract: Mice expressing a germline mutation in the phospholipase C-γ1-binding site of linker for activation of T cells (LAT) show progressive lymphoproliferation and ultimately die at 4-6 mo age. The hyperactivated T cells in these mice show defective TCR-induced calcium flux but enhanced Ras/ERK activation, which is critical for disease progression. Despite the loss of LAT-dependent phospholipase C-γ1 binding and activation, genetic analysis revealed RasGRP1, and not Sos1 or Sos2, to be the major Ras guanine exchange factor responsible for ERK activation and the lymphoproliferative phenotype in these mice. Analysis of isolated CD4(+) T cells from LAT-Y136F mice showed altered proximal TCR-dependent kinase signaling, which activated a Zap70- and LAT-independent pathway. Moreover, LAT-Y136F T cells showed ERK activation that was dependent on Lck and/or Fyn, protein kinase C-θ, and RasGRP1. These data demonstrate a novel route to Ras activation in vivo in a pathological setting.
authors.affiliation: Laboratory of Cellular and Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Kortum
authors.forename: Alexandre K
authors.initials: AK
authors.lastname: Rouquette-Jazdanian
authors.forename: Michihiko
authors.initials: M
authors.lastname: Miyaji
authors.forename: Robert K
authors.initials: RK
authors.lastname: Merrill
authors.forename: Evan
authors.initials: E
authors.lastname: Markegard
authors.forename: John M
authors.initials: JM
authors.lastname: Pinski
authors.forename: Amelia
authors.initials: A
authors.lastname: Wesselink
authors.forename: Nandan N
authors.initials: NN
authors.lastname: Nath
authors.forename: Clayton P
authors.initials: CP
authors.lastname: Alexander
authors.forename: Wenmei
authors.initials: W
authors.lastname: Li
authors.forename: Noemi
authors.initials: N
authors.lastname: Kedei
authors.forename: Jeroen P
authors.initials: JP
authors.lastname: Roose
authors.forename: Peter M
authors.initials: PM
authors.lastname: Blumberg
authors.forename: Lawrence E
authors.initials: LE
authors.lastname: Samelson
authors.forename: Connie L
authors.initials: CL
authors.lastname: Sommers
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000201:enzymology / Q000276:immunology*; D018450:Disease Progression; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology*; D018095:Germ-Line Mutation / Q000276:immunology; D020662:Guanine Nucleotide Exchange Factors / Q000502:physiology*; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology*; D008232:Lymphoproliferative Disorders / Q000201:enzymology / Q000235:genetics / Q000276:immunology*; D020935:MAP Kinase Signaling System / Q000235:genetics / Q000276:immunology*; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D051966:Phospholipase C gamma / Q000502:physiology; D010750:Phosphoproteins / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D020662:Guanine Nucleotide Exchange Factors; C491734:Lat protein, mouse; D008565:Membrane Proteins; D010750:Phosphoproteins; C112278:Rasgrp1 protein, mouse; D048049:Extracellular Signal-Regulated MAP Kinases; D051966:Phospholipase C gamma; C117399:Plcg1 protein, mouse