Abstract
Shp-2 is a ubiquitously expressed tyrosine phosphatase with two SH2 domains. Homozygous mutant mice with a targeted deletion of 65 amino acid residues in the N-terminal SH2 domain of Shp-2 die in utero at mid-gestation, with multiple defects in mesodermal patterning. To surpass the embryonic lethality in dissecting the Shp-2 function in cell growth and differentiation, we established homozygous Shp-2 mutant embryonic stem (ES) cell lines. Our previous data showed a severe suppression of hematopoietic cell differentiation from Shp-2 mutant ES cells. Here we demonstrate that development of cardiac muscle cells was dramatically delayed and impaired in embryoid bodies (EBs) of Shp-2 mutant origin. Shp-2 mutant ES cells failed to differentiate into epithelial and fibroblast cells in vitro. However, higher efficiency of secondary EB formation was observed from the mutant than the wild-type ES cells. Further, mutant ES cells were more sensitive than wild-type cells to the differentiation suppressing effect of leukemia inhibitory factor (LIF). In addition, mutant ES cells showed a reduced growth rate compared to wild-type cells. These results suggest that the Shp-2 tyrosine phosphatase is a positive regulator for both cell differentiation and proliferation, in contrast to the Src-family kinases which promote cell growth but block differentiation.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Cell Differentiation / physiology*
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Cell Division / physiology*
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Cell Line
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Cell Lineage
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Epithelial Cells / cytology
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Fibroblasts / cytology
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Gene Expression Regulation
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Growth Inhibitors / metabolism
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Growth Inhibitors / pharmacology
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Interleukin-6*
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Intracellular Signaling Peptides and Proteins
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Leukemia Inhibitory Factor
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Lymphokines / metabolism
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Lymphokines / pharmacology
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Mice
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MyoD Protein / genetics
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Myocardium / cytology
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Myogenin / genetics
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Myosin Heavy Chains / genetics
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Myosin Light Chains / genetics
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Protein Tyrosine Phosphatase, Non-Receptor Type 11
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Protein Tyrosine Phosphatase, Non-Receptor Type 6
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Protein Tyrosine Phosphatases / genetics
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Protein Tyrosine Phosphatases / physiology*
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SH2 Domain-Containing Protein Tyrosine Phosphatases
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Signal Transduction
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src Homology Domains / physiology*
Substances
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Growth Inhibitors
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Interleukin-6
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Intracellular Signaling Peptides and Proteins
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Leukemia Inhibitory Factor
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Lif protein, mouse
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Lymphokines
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MyoD Protein
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Myog protein, mouse
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Myogenin
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Myosin Light Chains
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Protein Tyrosine Phosphatase, Non-Receptor Type 11
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Protein Tyrosine Phosphatase, Non-Receptor Type 6
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Protein Tyrosine Phosphatases
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Ptpn11 protein, mouse
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Ptpn6 protein, mouse
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SH2 Domain-Containing Protein Tyrosine Phosphatases
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Myosin Heavy Chains