Defective activity of ERK-1 and ERK-2 mitogen-activated protein kinases in peripheral blood T lymphocytes from patients with systemic lupus erythematosus: potential role of altered coupling of Ras guanine nucleotide exchange factor hSos to adapter protein Grb2 in lupus T cells.
The integrity of the Ras/Raf/mitogen-activated protein kinase (MAPK) cascade is critical for maintenance of T cell tolerance, a process that fails in patients with systemic lupus erythematosus (SLE). In this study we have examined the activity of mitogen-activated protein kinases ERK-1 and ERK-2 in resting and TCR-activated peripheral blood T lymphocytes from patients with SLE. We also examined the binding of Ras guanine nucleotide exchange factor, human Son of Sevenless (hSos), to cytosolic adapter protein growth factor receptor-bound protein 2. T cells from lupus patients showed diminished catalytic activity and TCR-driven dual phosphorylation of ERK-1 and ERK-2 upon stimulation through the TCR/CD3 receptor, a defect that may be related to altered translocation of hSos to the Ras/Raf membrane complex and diminished nuclear translocation of trans-acting factor AP-1. Defective MAPK activity triggered by TCR/ CD3 activation may alter the coordination of signals needed for normal interleukin-2 production and maintenance of tolerance in lupus T cells.
Cedeño
Samandhy
S
Centro Nacional de Enfermedades Reumaticas, Division of Rheumatology, Hospital Universitario de Caracas, Venezuela.
Cifarelli
Domenico F
DF
Blasini
Ana M
AM
Paris
Magdalena
M
Placeres
Fabiola
F
Alonso
Guillermina
G
Rodriguez
Martin A
MA
D048868:Adaptor Proteins, Signal Transducing; D000293:Adolescent; D000328:Adult; D002467:Cell Nucleus / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D051380:GRB2 Adaptor Protein; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000097:blood / Q000201:enzymology*; D008297:Male; D008875:Middle Aged; D019950:Mitogen-Activated Protein Kinase 1 / Q000172:deficiency*; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000172:deficiency*; D011506:Proteins / Q000378:metabolism*; D013601:T-Lymphocytes / Q000201:enzymology*; D018808:Transcription Factor AP-1 / Q000378:metabolism; D020663:ras Guanine Nucleotide Exchange Factors / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D051380:GRB2 Adaptor Protein; C495948:GRB2 protein, human; D011506:Proteins; D018808:Transcription Factor AP-1; D020663:ras Guanine Nucleotide Exchange Factors; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases