Differential expression and molecular associations of Syk in systemic lupus erythematosus T cells.
Diminished expression of TCR zeta and reciprocal up-regulation and association of FcRgamma with the TCR/CD3 complex is a hallmark of systemic lupus erythematosus (SLE) T cells. In this study we explored whether differential molecular associations of the spleen tyrosine kinase Syk that preferentially binds to FcRgamma contribute to pathological amplification of signals downstream of this "rewired TCR" in SLE. We detected higher amounts of Syk expression and activity in SLE compared with normal T cells. Selective inhibition of the activity of Syk reduced the strength of TCR-induced calcium responses and slowed the rapid kinetics of actin polymerization exclusively in SLE T cells. Syk and ZAP-70 also associated differently with key molecules involved in cytoskeletal and calcium signaling in SLE T cells. Thus, while Vav-1 and LAT preferentially bound to Syk, phospholipase C-gamma1 bound to both Syk and ZAP-70. Our results show that differential associations of Syk family kinases contribute to the enhanced TCR-induced signaling responses in SLE T cells. Thus, we propose molecular targeting of Syk as a measure to control abnormal T cell responses in SLE.
Krishnan
Sandeep
S
Department of Cellular Injury, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA.
Juang
Yuang-Taung
YT
Chowdhury
Bhabadeb
B
Magilavy
Abigail
A
Fisher
Carolyn U
CU
Nguyen
Hang
H
Nambiar
Madhusoodana P
MP
Kyttaris
Vasileios
V
Weinstein
Arthur
A
Bahjat
Rena
R
Pine
Polly
P
Rus
Violeta
V
Tsokos
George C
GC
D048868:Adaptor Proteins, Signal Transducing / Q000276:immunology / Q000378:metabolism; D000328:Adult; D000368:Aged; D017252:CD3 Complex / Q000276:immunology / Q000378:metabolism; D020013:Calcium Signaling / Q000276:immunology*; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000276:immunology*; D008180:Lupus Erythematosus, Systemic / Q000201:enzymology / Q000276:immunology*; D008297:Male; D008565:Membrane Proteins / Q000276:immunology / Q000378:metabolism; D008875:Middle Aged; D051966:Phospholipase C gamma / Q000276:immunology / Q000378:metabolism; D011485:Protein Binding / Q000276:immunology; D011505:Protein-Tyrosine Kinases / Q000096:biosynthesis / Q000276:immunology*; D051567:Proto-Oncogene Proteins c-vav / Q000276:immunology / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism; D017452:Receptors, IgG / Q000276:immunology / Q000378:metabolism; D000072377:Syk Kinase; D013601:T-Lymphocytes / Q000201:enzymology / Q000276:immunology*; D015854:Up-Regulation / Q000276:immunology*; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000276:immunology / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D017252:CD3 Complex; D047908:Intracellular Signaling Peptides and Proteins; C110810:LAT protein, human; D008565:Membrane Proteins; D051567:Proto-Oncogene Proteins c-vav; D011948:Receptors, Antigen, T-Cell; D017452:Receptors, IgG; C496618:VAV1 protein, human; C054979:antigen T cell receptor, zeta chain; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human; D051966:Phospholipase C gamma