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Prepublished online as a Blood First Edition Paper on June 5, 2003; DOI 10.1182/blood-2003-04-1171. This Article Full Text (PDF) All Versions of this Article: 2003-04-1171v1 102/6/2074    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Chan, R. J Articles by Feng, G.-S. Search for Related Content PubMed PubMed Citation Articles by Chan, R. J Articles by Feng, G.-S. Social Bookmarking                   What's this? Submitted April 15, 2003 Accepted May 22, 2003 A definitive role of Shp-2 tyrosine phosphatase in mediating embryonic stem cell differentiation and hematopoiesis Rebecca J Chan, Scott A Johnson, Yanjun Li, Mervin C Yoder, and Gen-Sheng Feng* Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA Program in Signal Transduction Research, The Burnham Institute, La Jolla, CA, USA * Corresponding author; email: gfeng{at}burnham.org. Homozygous mutant (Shp-246-110) embryonic stem (ES) cells exhibit decreased hematopoiesis; however, the point at which Shp-2 is critical for ES cell differentiation to hematopoietic cells is unknown. We characterized the differentiation defect of Shp-246-110 ES cells by examining early points of differentiation, conducting LIF-stimulated biochemical analysis, and performing in vitro reconstitution studies with WT Shp-2. ES cell in vitro differentiation assays were employed to compare the differentiation of WT, Shp-246-110, and reconstituted ES cells to mesoderm, by measuring brachyury expression, to hemangioblasts, by measuring BL-CFC formation and flk-1 expression, and to hematopoietic progenitor colony forming cells, by performing secondary plating assays. LIF-stimulated phospho-Stat3, known to be critical for ES cell self-renewal and maintenance of an undifferentiated state, and phospho-Erk levels were examined by immunoblotting. ES cell survival, using annexin V staining, and 2° EB formation were also evaluated. Differentiation to both mesoderm and hemangioblasts was lower in Shp-246-110 cells compared to WT cells. Upon reconstitution with WT Shp-2, expression of brachyury and flk-1 and differentiation to hemangioblasts, primitive, and definitive hematopoietic progenitors were restored. LIF-stimulated phospho-Stat3 levels were higher while phospho-Erk levels were lower in Shp-246-110 ES cells than in WT and reconstituted cells, and the increased phospho-Stat3 levels correlated with increased Shp-246-110 ES cell 2° EB formation and survival. We conclude that normal Shp-2 function is critical for the initial step of ES cell differentiation to mesoderm and to hemangioblasts and acts within the LIF-gp130-Stat3 pathway to maintain a proper balance of ES cell differentiation, pluripotency, and apoptosis. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: Z. Yang, T. Kondo, C. S. Voorhorst, S. C. Nabinger, L. Ndong, F. Yin, E. M. Chan, M. Yu, O. Wurstlin, C. P. Kratz, et al. Increased c-Jun Expression and Reduced GATA2 Expression Promote Aberrant Monocytic Differentiation Induced by Activating PTPN11 Mutants Mol. Cell. Biol., August 15, 2009; 29(16): 4376 - 4393. [Abstract] [Full Text] [PDF] W. 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