Hematopoietic cell processes, such as survival, proliferation, and differentiation are tightly regulated and mediated by extra cellular signals. Dysregulation of the intracellular processes initiated by such signals causes malfunctioning of hematopoietic cells, and eventually leads to hematological disorders. Our long-term objective is to characterize the signaling pathways involving the SHP-2 and SHP-1 protein tyrosine phosphatases that regulate hematopoietic cell processes. A negative regulatory role for the hematopoietic cell specific phosphatase-SHP-1 in hematopoietic cell responses to a variety of external stimuli has been documented. However, the biological and biochemical function of SHP-2 in hematopoietic cell regulation remains largely unknown. We previously demonstrated that SHP-2 was required for erythroid, myeloid, and lymphoid development. Interestingly, defective primitive hematopoiesis caused by the SHP-2 mutation was partially rescued by an additional SHP-1 mutation in SHP-2/SHP-1 double mutant embryos, suggesting that SHP-2 and SHP-1 function oppositely in hematopoietic cell development. More recent laboratory studies show that SHP-2 and SHP-1 do distinctively regulate hematopoietic cell growth and survival. Based on our preliminary studies, we hypothesize that SHP-2 phosphatase plays critical roles in mediating specific hematopoietic cell processes, and cooperates with SHP-1 phosphatase to properly control hematopoietic cell behavior. To further characterize the role of SHP-2 and its functional interaction with SHP-1 phosphatase in hematopoietic cell regulation, we propose to: 1) Analyze the function of and the relationship between the SHP-2 and SHP-1 phosphatases in primitive hematopoietic development; 2) Investigate the role of SHP-2 phosphatase in determining hematopoietic stem/progenitor cell repopulating activity by using a dominant negative approach; and 3) Define the signaling mechanisms of SHP-2 and SHP-1 in regulating hematopoietic cell proliferation and survival. The dual potential early yolk sac precursor cell lines as well as SHP-2 mutant, SHP-1 mutant, and SHP-2/SHP-1 double mutant hematopoietic cell lines we established have provided us with a unique opportunity to accomplish these goals. The results of these experiments should yield new insights into the intracellular signaling regulation of hematopoiesis, which may lead to novel therapeutic approaches for certain blood disorders.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
7R01HL068212-04
Application #
7104773
Study Section
Hematology Subcommittee 2 (HEM)
Program Officer
Thomas, John
Project Start
2002-07-01
Project End
2007-12-16
Budget Start
2005-07-28
Budget End
2007-12-16
Support Year
4
Fiscal Year
2005
Total Cost
$347,625
Indirect Cost
Name
Case Western Reserve University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
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Seshadri, Madhav; Qu, Cheng-Kui (2016) Microenvironmental regulation of hematopoietic stem cells and its implications in leukemogenesis. Curr Opin Hematol 23:339-45
Yu, Bing; Liu, Wei; Yu, Wen-Mei et al. (2013) Targeting protein tyrosine phosphatase SHP2 for the treatment of PTPN11-associated malignancies. Mol Cancer Ther 12:1738-48
Xu, Dan; Zheng, Hong; Yu, Wen-Mei et al. (2013) Activating mutations in protein tyrosine phosphatase Ptpn11 (Shp2) enhance reactive oxygen species production that contributes to myeloproliferative disorder. PLoS One 8:e63152
Liu, Wei; Yu, Bing; Xu, Gang et al. (2013) Identification of cryptotanshinone as an inhibitor of oncogenic protein tyrosine phosphatase SHP2 (PTPN11). J Med Chem 56:7212-21
Yu, Wen-Mei; Liu, Xia; Shen, Jinhua et al. (2013) Metabolic regulation by the mitochondrial phosphatase PTPMT1 is required for hematopoietic stem cell differentiation. Cell Stem Cell 12:62-74
Zheng, Hong; Li, Shanhu; Hsu, Peter et al. (2013) Induction of a tumor-associated activating mutation in protein tyrosine phosphatase Ptpn11 (Shp2) enhances mitochondrial metabolism, leading to oxidative stress and senescence. J Biol Chem 288:25727-38
Hsu, Peter; Qu, Cheng-Kui (2013) Metabolic plasticity and hematopoietic stem cell biology. Curr Opin Hematol 20:289-94
Liu, Alice M; Qu, William W; Liu, Xia et al. (2012) Chromosomal instability in in vitro cultured mouse hematopoietic cells associated with oxidative stress. Am J Blood Res 2:71-6
Liu, Xia; Zheng, Hong; Qu, Cheng-Kui (2012) Protein tyrosine phosphatase Shp2 (Ptpn11) plays an important role in maintenance of chromosome stability. Cancer Res 72:5296-306

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