: Within the cytosolic tails of the B cell antigen receptor Ig-alpha and Ig-beta chains are conserved motifs (immunoreceptor tyrosine-based activation motifs or ITAMs) that are required for the recruitment and activation of the tyrosine kinase Syk. The direct recruitment of the linker molecule BLNK to a phosphorylated Ig-alpha non-ITAM tyrosine (Y204) couples the receptor to several downstream pathways. These, and others studies, demonstrate that non-ITAM motifs within the cytosolic tails of Ig-alpha and Ig-beta are important for receptor signaling and B cell development. In this grant proposal, we will determine how receptor activated kinases utilize linker molecules to couple to distal signaling pathways. We will also determine how these mechanisms are regulated and if their regulation can decide cell fate. In a second line of investigation, we will examine how Ig-alpha and Ig-beta contribute to B cell development. By analyzing a developmental model, we will be able to perform a structural and functional dissection of the B cell antigen receptor not possible using purely biochemical approaches. Our central hypothesis is that the B cell antigen receptor directly recruits multiple signaling molecules required for both the activation of specific signaling pathways and for the development, maturation and activation of B cells. This hypothesis will be tested in the following three Specific Aims:
Aim 1 : To determine the mechanisms and consequences of Ig-alpha non-ITAM tyrosine phosphorylation. We will examine the hypothesis that BLNK recruitment to Ig-alpha nucleates a multimeric signaling complex necessary for the activation and integration of several signaling pathways.
Aim 2 : To determine the relative contributions of Ig-alpha and Ig-beta to B cell antigen receptor function. We hypothesize that Ig-beta activates only a subset of the pathways activated by Ig-alpha. This will be examined using chimeric receptors containing Ig-alpha or Ig-beta. We will also determine if altered signaling pathways characteristic of anergy can arise from hypo-phosphorylation of Y204.
Aim 3 : To examine how Ig-alpha and Ig-beta determine B cell development. We will examine the hypothesis that specific domains in Ig-alpha/Ig-beta define windows of development. For these experiments, we will utilize retrovirally reconstituted lg-beta deficient mice.
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