Present knowledge suggests that the B cell antigen receptor (BCR) complex is comprised of a series of structures that include: membrane immunoglobulin (mIg), the Ig-associated proteins Ig-alpha, Ig-beta, and Ig-gamma, and cytoplasmic enzymes and cytoskeletal components. It is certainly possible that other molecules not yet determined constitute a part of this apparatus. Interactions among these structures result in a diverse array of cellular effects, such as proliferation, apoptosis, anergy, and differentiation. This proposal will focus on the definition of variant truncated forms of the Ig-alpha and Ig-beta proteins in man. The hypothesis to be addressed is that these variant mRNA forms arise by alternative splicing mechanisms, and that they code for proteins that modulate the B cell response to antigen, either because they cannot interact well with mIg, or because they interact with membrane and/or intracytoplasmic molecules other than, or in addition to, those usually bound by the native Ig-alpha/beta forms. Specifically, we will document that variant processing forms of these mRNAs and proteins exist in human B cells, and compare these structures with those of the native molecules. Our preliminary data suggest that at least two distinct mRNA forms of both genes exist that differ in regions encoding portions of the external domains of the two proteins. Attempts will be made to identify intracytoplasmic variants of human Ig-alpha and Ig-beta. In addition, we will compare the expression of the native and variant forms in B cells tat various stages of maturation, activation and differentiation. We will attempt to determine whether the variant protein forms, because of their altered protein structures, associate and/or interact with different proteins than those that associate with the native Ig-alpha and Ig-beta proteins. Finally, we will determine the functional roles of the native and variant forms in transporting the BCR to the cell surface, of transducing an activation signal, and of augmenting or antagonizing the transduction of signals by the native forms of these molecules. These studies will involve selected B cell lines and B cell knock-outs transfected with variant forms that will be signalled by various stimuli.
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