Characterization of Twixt: a novel membrane adaptor protein in B cells

描述（由申请人提供）：我们最近完成了第一项在静息和bcr刺激的原代B细胞中酪氨酸磷酸化底物的综合研究。在这项工作中，我们专注于一种新的跨膜衔接蛋白，称为Twixt，因为它具有新颖性，在B细胞中选择性表达，并且在填补我们对BCR信号传导的理解中的知识空白方面具有潜在的重要性-即BLNK如何被诱导招募到BCR复合体。在拟议的工作中，我们将确定BCR和其他受体如何招募和利用Twixt来影响下游信号传导。这些数据将为解释在twixt缺陷小鼠中观察到的表型提供一个机制框架，这些表型将在第二Aim中生成和分析。完成拟议的研究将确立Twixt作为BCR信号传导的核心参与者的突出地位，或揭示更具选择性的作用。

DESCRIPTION (provided by applicant): We recently completed the first comprehensive study of tyrosine phosphorylated substrates in resting and BCR-stimulated primary B cells. From this effort, we focused on a novel transmembrane adaptor protein, termed Twixt, due to its novelty, selective expression in B cells and potential importance in fulfilling a knowledge gap in our understanding of BCR signaling - namely how BLNK is inducibly recruited to the BCR complex. In the proposed work, we will determine how Twixt is recruited and utilized by the BCR and perhaps other receptors to effect downstream signaling. These data will provide a mechanistic framework for interpreting the phenotypes observed in Twixt-deficient mice, which will be generated and analyzed in the second Aim. Completion of the proposed studies will establish the prominence of Twixt as a central player in BCR signaling, or reveal a more selective role. PUBLIC HEALTH RELEVANCE: Signaling via the B cell antigen receptor (BCR) determines the fate of the B cell in terms of continued survival, proliferation and differentiation. These signals are relayed to the nucleus to bring about changes in gene expression that will decide B cell fate. The nature of these signals remains incomplete - as is our understanding of how aberrant signal transduction can precipitate B cell autoimmunity or transformation. In the proposed work we will characterize a novel B cell signaling adaptor that may be quite important in parsing this early membrane-proximal signal to engage downstream effector pathways.