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.
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