title: Differential expression and molecular associations of Syk in systemic lupus erythematosus T cells.
abstract: 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.
authors.affiliation: Department of Cellular Injury, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA.
authors.forename: Sandeep
authors.initials: S
authors.lastname: Krishnan
authors.forename: Yuang-Taung
authors.initials: YT
authors.lastname: Juang
authors.forename: Bhabadeb
authors.initials: B
authors.lastname: Chowdhury
authors.forename: Abigail
authors.initials: A
authors.lastname: Magilavy
authors.forename: Carolyn U
authors.initials: CU
authors.lastname: Fisher
authors.forename: Hang
authors.initials: H
authors.lastname: Nguyen
authors.forename: Madhusoodana P
authors.initials: MP
authors.lastname: Nambiar
authors.forename: Vasileios
authors.initials: V
authors.lastname: Kyttaris
authors.forename: Arthur
authors.initials: A
authors.lastname: Weinstein
authors.forename: Rena
authors.initials: R
authors.lastname: Bahjat
authors.forename: Polly
authors.initials: P
authors.lastname: Pine
authors.forename: Violeta
authors.initials: V
authors.lastname: Rus
authors.forename: George C
authors.initials: GC
authors.lastname: Tsokos
mesh_terms: 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
chemical_list: 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