REGULATION OF BCR MEDIATED SIGNAL TRANSDUCTION BY CD45

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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.