T and B lymphocytes play critical roles in the normal immune response. However, aberrant activation of these cells result in a variety of autoimmune disorders and cancers. Activation of T- and B-cells by foreign antigens are mediated by T- and B-cell antigen receptors, respectively, and involves a cascade of biochemical events the culminate in a host response against foreign pathogens. Protein tyrosine kinases (PTKs) play an integral role in T- and B-cell activation and are involved in the initiating events in this cascade. The experiments proposed in this proposal will dissect how the Syk PTK is involved in both T-and B-cell function. This PTK is critical for the development and function of B cells and may also have a role in the function of T cells. An understanding of how the Syk PTK functions in B-cells will provide a greater knowledge of signal transduction mechanisms in lymphocytes and greater insight into regulatory mechanisms of PTKs. In addition, these studies may provide additional mechanistic information that may serve as the basis for more rational therapeutic interventions in drug design for cancer, autoimmune diseases and transplantation rejection.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA071516-02
Application #
2443274
Study Section
Special Emphasis Panel (ZRG2-ALY (01))
Project Start
1996-07-01
Project End
1999-06-30
Budget Start
1997-07-01
Budget End
1998-06-30
Support Year
2
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
062761671
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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Pappu, R; Cheng, A M; Li, B et al. (1999) Requirement for B cell linker protein (BLNK) in B cell development. Science 286:1949-54
Ishiai, M; Kurosaki, M; Pappu, R et al. (1999) BLNK required for coupling Syk to PLC gamma 2 and Rac1-JNK in B cells. Immunity 10:117-25
Minegishi, Y; Rohrer, J; Coustan-Smith, E et al. (1999) An essential role for BLNK in human B cell development. Science 286:1954-7
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Wong, J; Straus, D; Chan, A C (1998) Genetic evidence of a role for Lck in T-cell receptor function independent or downstream of ZAP-70/Syk protein tyrosine kinases. Mol Cell Biol 18:2855-66
Fu, C; Turck, C W; Kurosaki, T et al. (1998) BLNK: a central linker protein in B cell activation. Immunity 9:93-103
Bubeck Wardenburg, J; Pappu, R; Bu, J Y et al. (1998) Regulation of PAK activation and the T cell cytoskeleton by the linker protein SLP-76. Immunity 9:607-16
Futterer, K; Wong, J; Grucza, R A et al. (1998) Structural basis for Syk tyrosine kinase ubiquity in signal transduction pathways revealed by the crystal structure of its regulatory SH2 domains bound to a dually phosphorylated ITAM peptide. J Mol Biol 281:523-37

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