REGULATION OF BCR MEDIATED SIGNAL TRANSDUCTION BY CD45

描述：（改编自研究者摘要）：本研究的总体目标 竞争性更新的应用是了解分子机制， 其中CD 45酪氨酸磷酸酶调节BCR信号转导阈值。工作 包括主要研究者在内的多个实验室 表明CD 45是正常B细胞发育所必需的，而B细胞 由BCR或II类MHC分子介导的活化。使用CD 45 缺乏细胞系，Justement博士已经表明，CD 45的功能， 调节蛋白质酪氨酸磷酸化，至少部分地，但不是唯一地， 通过其对B细胞中Src家族PTK，特别是林恩的作用。CD 45也 影响许多下游事件，包括细胞外钙离子的流入 以及包括Erk 2激活的远端途径的激活。值得关注的是 他已经证明，在CD 45缺陷的细胞中， 细胞，包括Syk激酶的诱导磷酸化。其他 磷酸化事件也被保留，包括CD 22磷酸化和 SHP-1与CD 22的结合。这促使他进一步探索CD 45在 该建议通过：1）确定下游信令中的改变是否 与CD 45丢失相关的过程是由于特定Src 家族激酶和蛋白酪氨酸磷酸酶SHP-1; 2）鉴定CD 45 通过使用底物捕获突变体和酵母在B细胞中的底物 表达克隆的三杂交方法;和3）通过定义调控因子， CD 45的PTP结构域II内区域的功能。特别关注的是 酪蛋白激酶II的相互作用和先前鉴定的CKII的作用 PTP结构域II中的丝氨酸磷酸化位点。

DESCRIPTION: (Adapted from Investigator's Abstract): The overall goal of this competitive renewal application is to understand the molecular mechanisms by which the CD45 tyrosine phosphatase regulates BCR signaling threshold. Work from a number of laboratories including that of the principal investigator has demonstrated that CD45 is required for normal B cell development and B cell activation mediated by the BCR or by class II MHC molecules. Using CD45 deficient cells lines, Dr. Justement has shown that CD45 functions by regulating protein tyrosine phosphorylation, at least in part, but not solely, through its action on Src family PTKs, particularly Lyn, in B cells. CD45 also influences numerous downstream events including influx of extracellular calcium and activation of distal pathways including Erk2 activation. It is noteworthy that he has shown that some signaling events are preserved in CD45 deficient cells, including inducible phosphorylation of the Syk kinase. Other phosphorylation events are also preserved, including CD22 phosphorylation and SHP-1 binding to CD22. This has led him to further explore the role of CD45 in this proposal by: 1) determining whether alterations in downstream signaling processes associated with CD45 loss are due to dysregulation of specific Src family kinases and the protein tyrosine phosphatase SHP-1; 2) identifying CD45 substrates in B cells through the use of substrate trapping mutants and a yeast tri-hybrid method of expression cloning; and 3) by defining the regulatory function of regions within PTP domain II of CD45. Particular focus is on an interaction of Casein Kinase II and the role of previously identified CKII serine phosphorylation sites in PTP domain II.