We have exploited the paradigm of positive/negative signaling in B cells to dissect critical biochemical signaling events that promote B cell activation. Thus, in the earlier funding period, we identified the inositol 5-phosphatase SHIP as a primary contributor in the B cell negative signaling process. First, SHIP acts as a SHIP domain competitor for GRB2 binding to phospho-Shc, thereby blocking induction of the Ras pathway. Second, although as yet unexplored in any receptor system, SHIP consumes 3-phosphorylated phosphoinositides and thus blocks signaling pathways downstream of PtdIns 3-kinase. PtdIns 3-kinase plays an important but largely undefined role in a wide variety of biological processes, including transformation and proliferation, antigen uptake, phagocytosis, and cellular invasion by pathogens. Our paradigm of B cell positive/negative signaling may be ideal to investigate the precise role of 3-phosphorylated phosphoinositides in these processes, because of the enzymatic specificity of SHIP towards PtdIns 3-kinase products and because only small changes in the stimulating reagent [F(ab')2 or intact anti-Ig] are necessary to promote or prevent SHIP action. Here, we propose experiments to better understanding signaling pathways of B cell activation and the negative influence of SHIP on the associated downstream biochemical events. Such information may reveal novel therapeutic targets in a variety of pathologic conditions and contribute to the etiology of such diseases.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA064268-08
Application #
6376080
Study Section
Immunobiology Study Section (IMB)
Program Officer
Hackett, Charles J
Project Start
1994-08-01
Project End
2004-04-30
Budget Start
2001-05-01
Budget End
2002-04-30
Support Year
8
Fiscal Year
2001
Total Cost
$251,112
Indirect Cost
Name
Oklahoma Medical Research Foundation
Department
Type
DUNS #
937727907
City
Oklahoma City
State
OK
Country
United States
Zip Code
73104
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Nakamura, Koji; Kouro, Taku; Kincade, Paul W et al. (2004) Src homology 2-containing 5-inositol phosphatase (SHIP) suppresses an early stage of lymphoid cell development through elevated interleukin-6 production by myeloid cells in bone marrow. J Exp Med 199:243-54
Phee, H; Rodgers, W; Coggeshall, K M (2001) Visualization of negative signaling in B cells by quantitative confocal microscopy. Mol Cell Biol 21:8615-25