A Phospholipase C-gamma 1-Independent, RasGRP1-ERK-Dependent Pathway Drives Lymphoproliferative Disease in Linker for Activation of T Cells-Y136F Mutant Mice

作者：Kortum Robert L; Rouquette Jazdanian Alexandre K; Miyaji Michihiko; Merrill Robert K; Markegard Evan; Pinski John M; Wesselink Amelia; Nath Nandan N; Alexander Clayton P; Li Wenmei; Kedei Noemi; Roose Jeroen P; Blumberg Peter M; Samelson Lawrence E; Sommers Connie L^*

来源：The Journal of Immunology, 2013, 190(1): 147-158.

DOI：10.4049/jimmunol.1201458

Mice expressing a germline mutation in the phospholipase C-gamma 1-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-gamma 1 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-theta, and RasGRP1. These data demonstrate a novel route to Ras activation in vivo in a pathological setting. The Journal of Immunology, 2013, 190: 147-158.

• 出版日期2013-1-1