The division between normal cellular homeostasis and malignant transformation is maintained by regulation of the balance between cell death and survival, proliferation and differentiation. Cell surface receptors, whose signals affect the balance between these cell fates, often do so in a manner that depends upon the differentiation and activation state of the cell and the strength of the signal generated. The B cell antigen receptor (BCR) can generate signals that lead to a variety of outcomes depending upon the developmental stage of the B cell and the degree and persistence of receptor aggregation. Genetic and biochemical studies have shown that various forms of the BCR are expressed at defined stages of B cell development. Although expression of these receptors is required for development of B cells, we currently have little understanding of how signals are generated at these developmental checkpoints. We hypothesize that these different receptor structures exist to chaperone the BCR-associated signaling molecules Igot and IgB to the plasma membrane. At the plasma membrane, Iga and IgB generate signals in a ligand-independent manner. This hypothesis maintains that the BCR and BCRlike structures on developing B cells are capable of ligand-dependent (in the case of the mature BCR) as well as ligand-independent functions (all stages of BCR expression). The existence, regulation, and biological relevance of these ligand-independent """"""""tonic"""""""" signals represent the broad goals of the proposed studies. Specifically, in Specific Aim 1 we will determine the biological relevance of ligandindependent tonic signaling and to what extent targeting Igct/IgB complexes to the plasma membrane defines the minimal requirement for positive selection at defined checkpoints in B cell development. In studies planned for Specific Aim 2, we expect to define the structural requirements for BCR tonic signaling in the context of positive selection during B cell development and survival in the periphery. Finally, in Specific Aim 3 we will determine whether the cellular context of the expression of ITAMcontaining proteins affects the regulation of constitutive signaling and the importance of this contextual expression to oncogenic potential. The rationale for this aim in the context of the proposed studies is that several oncogenic viruses encode proteins with ITAM motifs in their cytoplasmic domains. Often expressed in non-hematopoietic cells, we wish to compare tonic signaling through one of these ITAMs in the context of B cells and epithelial cells, both of which are pathologically-relevant targets for this expression. In so doing, we believe that this will allow us to better define the regulatory processes involved in TIAM-dependent tonic signaling as well as explore the possibility that expression of ITAM proteins in non-hematopoietic cells may promote transformation.
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