Dok-1 and Dok-2 are negative regulators of T cell receptor signaling.

Int Immunol 2007 Apr 27;19(4):487-95. Epub 2007 Feb 27.

Department of Cell Regulation, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.

Interaction of the TCR complex with self- or foreign peptides is a central event in the immune responses. Upon TCR stimulation, a protein-tyrosine kinase (PTK), ZAP-70, is recruited to signaling units of the TCR complex, such as TCRzeta, to play an essential role in T cell activation. Here, we find that mice lacking adaptor proteins Dok-1 and Dok-2 show augmented responses to thymus-dependent, but not thymus-independent, antigens, and that their T cells show elevated responses to TCR stimulation, including the activation of ZAP-70 and subsequent proliferation and cytokine production. Furthermore, the forced expression of Dok-1 or Dok-2 in a CD3(+)CD4(+) T cell clone inhibited the activation of ZAP-70 upon TCR stimulation. Interestingly, the Dok-1 and Dok-2 COOH-terminal moieties bearing the src homology 2 target motifs were dispensable for this negative regulation, even though they are crucial for the known adaptor function of Dok-family proteins. Thus, by an as yet unidentified mechanism, Dok-1 and Dok-2 play an essential role in the negative regulation of TCR signaling. Consistently, all mice lacking these proteins exhibited elevated titers of antibodies to double-stranded DNA and developed lupus-like renal disease.

Download full-text PDF

Source
https://academic.oup.com/intimm/article-lookup/doi/10.1093/i
Publisher Site
http://dx.doi.org/10.1093/intimm/dxm015DOI Listing
April 2007

Publication Analysis

Top Keywords

dok-1 dok-2
20
tcr stimulation
12
activation zap-70
8
tcr complex
8
responses tcr
8
negative regulation
8
mice lacking
8
essential role
8
play essential
8
tcr
6
dok-1
5
augmented responses
4
proteins exhibited
4
dok-2 augmented
4
exhibited elevated
4
dok-2
4
responses thymus-dependent
4
dok-2 cooh-terminal
4
consistently mice
4
thymus-independent antigens
4

Similar Publications

Dok-1 and Dok-2 are negative regulators of lipopolysaccharide-induced signaling.

J Exp Med 2005 Feb;201(3):333-9

Department of Cell Regulation, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.

Endotoxin, a bacterial lipopolysaccharide (LPS), causes fatal septic shock via Toll-like receptor (TLR)4 on effector cells of innate immunity like macrophages, where it activates nuclear factor kappaB (NF-kappaB) and mitogen-activated protein (MAP) kinases to induce proinflammatory cytokines such as tumor necrosis factor (TNF)-alpha. Dok-1 and Dok-2 are adaptor proteins that negatively regulate Ras-Erk signaling downstream of protein tyrosine kinases (PTKs). Here, we demonstrate that LPS rapidly induced the tyrosine phosphorylation and adaptor function of these proteins. Read More

View Article and Full-Text PDF
February 2005

Cutting edge: Dok-1 and Dok-2 adaptor molecules are regulated by phosphatidylinositol 5-phosphate production in T cells.

J Immunol 2009 Apr;182(7):3974-8

Institut National de la Santé et de la Recherche Médicale, Centre de Recherche en Cancérologie de Marseille, France.

Downstream of tyrosine kinase (Dok) proteins Dok-1 and Dok-2 are involved in T cell homeostasis maintenance. Dok protein tyrosine phosphorylation plays a key role in establishing negative feedback loops of T cell signaling. These structurally related adapter molecules contain a pleckstrin homology (PH) domain generally acting as a lipid/protein-interacting module. Read More

View Article and Full-Text PDF
April 2009

Dok-1 is a positive regulator of IL-4 signalling and IgE response.

J Biochem 2007 Aug 7;142(2):257-63. Epub 2007 Sep 7.

Department of Cell Regulation, Medical Research Institute, Tokyo Medical and Dental University, Yushima 1-5-45, Bunkyo-ku, Tokyo 113-8510.

Interleukin-4 (IL-4) plays an essential role in the control of humoral immunity by regulating lymphocyte proliferation and differentiation, including the T helper type 2 lineage commitment of CD4(+) T cells as well as the isotype switching to IgE in B cells. The adaptor protein Dok-1 is known to have an essential role in the negative regulation of a variety of cytokine signalling events. However, here we have found that the loss of Dok-1 impaired the proliferative response of CD4(+) T cells and B cells to IL-4. Read More

View Article and Full-Text PDF
August 2007

Galectin-1 specifically modulates TCR signals to enhance TCR apoptosis but inhibit IL-2 production and proliferation.

J Immunol 1999 Jan;162(2):799-806

Department of Microbiology and Immunology, University of California, Los Angeles, School of Medicine, 90095, USA.

Galectin-1 is an endogenous lectin expressed by thymic and lymph node stromal cells at sites of Ag presentation and T cell death during normal development. It is known to have immunomodulatory activity in vivo and can induce apoptosis in thymocytes and activated T cells (1-3). Here we demonstrate that galectin-1 stimulation cooperates with TCR engagement to induce apoptosis, but antagonizes TCR-induced IL-2 production and proliferation in a murine T cell hybridoma and freshly isolated mouse thymocytes, respectively. Read More

View Article and Full-Text PDF
January 1999