The molecular mechanism of signal transduction that regulates embryonic hematopoiesis is poorly understood. Shp-2, a cytoplasmic tyrosine phosphatase that contains two SH2 domains, participates in signaling downstream of cytokine receptors. Using a gene targeting approach, we have created a Shp-2 mutant allele by deleting amino acids 46-110 in the N-terminal SH2 domain. Mice homozygous for this mutation die in utero at mid- gestation with defects in posterior development and organization of axial structures. Our in vitro ES cells differentiation experiments suggest an important role for Shp-2 in erythroid and myeloid cell differentiation. On this project, we will center our focus on dissecting the Shp-2 function in the hierarchial development of hematopoietic stem/progenitor cells.
My specific aims are: 1). to determine the role of Shp-2 phosphatase on the commitment of a common precursor for hematopoietic and endothelial cells and to uncover the alteration of cellular responses to cytokines by the Shp-2 mutation during hematopoietic cell differentiation; II). to examine the effect of the Shp-2 mutation on both the hematopoietic stem cells and the microenvironment in blood forming tissues in vivo, using chimeric animals containing Shp-2-/- cells; III). to specifically assess the involvement of Shp-2 in T and B lymphocyte development using the RAG-2 complementation system and to dissect the unique function of Shp-2 in lymphocyte signaling; IV). to reconstitute the developmental program of blood cells in Shp-2 mutant ES cells and to elucidate the molecular basis for Shp-2 function in mediating blood cell development; V). to isolate and characterize another ES cell line with an Shp-2 null mutation. This study will provide fundamental insight into the role of a tyrosine phosphatase in cytoplasmic signaling pathways that control the commitment, differentiation and survival of hematopoietic stem cells.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA078606-04
Application #
6513302
Study Section
Hematology Subcommittee 2 (HEM)
Program Officer
Mufson, R Allan
Project Start
1999-05-01
Project End
2004-02-29
Budget Start
2002-03-01
Budget End
2003-02-28
Support Year
4
Fiscal Year
2002
Total Cost
$270,264
Indirect Cost
Name
Sanford-Burnham Medical Research Institute
Department
Type
DUNS #
009214214
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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Wu, Dongmei; Pang, Yuhong; Ke, Yuehai et al. (2009) A conserved mechanism for control of human and mouse embryonic stem cell pluripotency and differentiation by shp2 tyrosine phosphatase. PLoS One 4:e4914
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Pan, Yi; Carbe, Christian; Powers, Andrea et al. (2008) Bud specific N-sulfation of heparan sulfate regulates Shp2-dependent FGF signaling during lacrimal gland induction. Development 135:301-10
Ke, Yuehai; Zhang, Eric E; Hagihara, Kazuki et al. (2007) Deletion of Shp2 in the brain leads to defective proliferation and differentiation in neural stem cells and early postnatal lethality. Mol Cell Biol 27:6706-17
Ke, Y; Wu, D; Princen, F et al. (2007) Role of Gab2 in mammary tumorigenesis and metastasis. Oncogene 26:4951-60
Chan, Rebecca J; Feng, Gen-Sheng (2007) PTPN11 is the first identified proto-oncogene that encodes a tyrosine phosphatase. Blood 109:862-7
Feng, Gen-Sheng (2007) Shp2-mediated molecular signaling in control of embryonic stem cell self-renewal and differentiation. Cell Res 17:37-41
Ke, Yuehai; Lesperance, Jacqueline; Zhang, Eric E et al. (2006) Conditional deletion of Shp2 in the mammary gland leads to impaired lobulo-alveolar outgrowth and attenuated Stat5 activation. J Biol Chem 281:34374-80

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