Many important physiological processes are regulated by protein-tyrosyl phosphorylation, which in turn is regulated by protein-tyrosyl kinases (PTKs) and protein- tyrosyl phosphatases (PTPs). Oligomeric antigen receptors, such as the B cell receptor (BCR), T cell receptor, and Fc receptors, signal through receptor- associated PTKs. For example, the BCR is associated with src- family PTKs Lyn, Fyn, and Blk, which activate the downstream Btk and Syk PTKs, leading to tyrosyl phosphorylation of specific substrates. These substrates include BCR subunits and accessory molecules and secondary signaling molecules containing SH2 and SH3 domains. Abnormalities of tyrosyl phosphorylation in lymphoid cells can lead to hyper-proliferative disorders such as lymphomas, as well as defective- or auto-immunity. Much has been learned about how PTKs regulate normal physiology and how certain abnormal PTKs cause disease, but little is known about the role of specific PTPs in normal- or patho-physiology. The goal of this research is to define how the SH2-containing non-transmembrane tyrosine phosphatase SHPTP1 controls BCR signal transduction, and the consequences of loss of this regulation on B cell signalling and functions in cultured cells and transgenic mice. Genetic and biochemical data suggest that SHPTP1 is a negative regulator of many PTK pathways. SHPTP1 mutations cause the motheaten (me) mouse, which has multiple B cell abnormalities, including depletion of B cell precursors, a rightward shift in B cell development, and an excess of B1 cells. In preliminary studies, the applicant created a set of isogenic mature B cell lines from normal and me mice, and has shown that SHPTP1 is part of the BCR complex, and functions to specifically regulate BCR-associated PTKs. The applicant proposes to define the mechanism of regulation of BCR signaling by SHPTP1 in molecular detail. The molecular details by which SHPTP1 regulates BCR- associated PTKs will be determined by peptide mapping experiments. Direct SHPTP1 substrates will be identified by a """"""""PTP- dead"""""""" trapping approach. The consequences of isolated and combined dysregulation of SHPTP1- regulated PTKs will be determined biochemically and biologically, by expressing activated PTK mutants. The mechanism by which SHPTP1 is associated with the BCR complex will be elucidated, and the biochemical and biological consequences of failure to be released from the BCR will be determined. SHPTP1 structural domains important for B cell functions will be defined by site-specific mutagenesis, and the molecular basis for SH-PTP specificity examined using SHPTP1/SHPTP2 chimeras. Finally, the in vivo significance of SHPTP1 regulation of B cell signaling will be assessed by creating transgenic mice expressing a dominant negative SHPTP1 mutant selectively in the B cell lineage, and by expressing B cell targeted, activated versions of PTKs that are normally regulated by SHPTP1. The results of the proposed studies should yield new insights into how PTPs regulate B cell signalling, and may have implications for lymphomagenesis and/or autoimmunity.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Pathology B Study Section (PTHB)
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Mccarthy, Susan A
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Beth Israel Deaconess Medical Center
United States
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