The most proximal signaling event known to occur following engagement of the T cell antigen receptor (TCR) is stimulation of a cascade of protein tyrosine kinases (PTK). Following this, other second messenger pathways are activated leading to the appropriate distal response. Recently there has been considerable attention focussed on how signaling cascades are intergrated. The overall goal of the proposed experiments is to continue the structural and fucntional characterization of SLP-76 and its novel associated protein SAP-130. To achieve this goal, the investigator proposes to address further the biochemical features of SLP-76 by identifying the kinases and phosphatases which regulate its phosphorylation as well as localizing SLP-76 within the cell and determining what other molecules SLP-76 binds.
The second aim i s to investigate further the function of SLP-76 by asking questions regarding the consequence of serine phosphoryaltion of this molecule as well as pursuing the relationship between SLP-76 and vav. Additionally it is proposed to study the tissues and cellular subsets which express SLP-76 and to create a mouse deficient in SLP-76 expression via targeted gene disruption.
The third aim i s to study the biochemistry of SAP-130 by asking about its phosphorylation and protein associations.
The final aim i s to begin to assess SAP-130 function by addressing the consequences of its overexpression and the importance of its tyrosine phosphorylation. Additionally, the investigator is interested in understanding better the functional and biochemical relationship between SAP-130 and SLP-76. It is hoped that these studies will shed further light into the regulation of signal transduction in immune cells and provide data that will be useful in the treatment of diseases related to immune dysfunction.
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