Stimulation of t he B-cell antigen receptor (BCR) triggers the activation of at least 3 families of protein tyrosine kinases (PTKs). The sequential activation of these PTKs orchestrates a cascade of downstream signaling events, including activation of phospholipase C (PLC), and phosphorylation of the Shc adaptor protein and the Vav protooncogene. These proteins, in turn, drive the increases in cytoplasmic free Ca2+, Ras activation, and the activation of MAP kinases that couple BCR engagement to cell-cycle entry and alterations in gene expression. The investigator has identified two novel adapter proteins, designated BLNK- 1 and BLNK-2, that bind to PLC-gamma, Grb2, and Vav. These proteins exhibit sequence and functional homologies to the slp-76 adapter protein that appears to play a central role in signal transduction through the T-cell antigen receptor (TCR).
The specific aims are: (1) to characterize BLNK-1 and BLNK-2 at the molecular and biochemical levels, (2) to define the biochemical and functional interactions of BLNK-1 and BLNK-2 with PLC-gamma, Grb2 and Vav, (3) to identify the phosphorylation sites within BLNK-1, and (4) to use genetic approaches to understand the role of BLNK proteins in B-cell development and normal B-cell function.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI042787-01
Application #
2590946
Study Section
Experimental Immunology Study Section (EI)
Project Start
1998-02-01
Project End
2003-01-31
Budget Start
1998-02-01
Budget End
1999-01-31
Support Year
1
Fiscal Year
1998
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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Kabak, Shara; Skaggs, Brian J; Gold, Michael R et al. (2002) The direct recruitment of BLNK to immunoglobulin alpha couples the B-cell antigen receptor to distal signaling pathways. Mol Cell Biol 22:2524-35
Benschop, R J; Brandl, E; Chan, A C et al. (2001) Unique signaling properties of B cell antigen receptor in mature and immature B cells: implications for tolerance and activation. J Immunol 167:4172-9
Kelly, M E; Chan, A C (2000) Regulation of B cell function by linker proteins. Curr Opin Immunol 12:267-75
Wong, J; Ishiai, M; Kurosaki, T et al. (2000) Functional complementation of BLNK by SLP-76 and LAT linker proteins. J Biol Chem 275:33116-22
Ishiai, M; Kurosaki, M; Inabe, K et al. (2000) Involvement of LAT, Gads, and Grb2 in compartmentation of SLP-76 to the plasma membrane. J Exp Med 192:847-56
Bonilla, F A; Fujita, R M; Pivniouk, V I et al. (2000) Adapter proteins SLP-76 and BLNK both are expressed by murine macrophages and are linked to signaling via Fcgamma receptors I and II/III. Proc Natl Acad Sci U S A 97:1725-30
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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