Abstract
Shp-1, Shp-2 and corkscrew comprise a small family of cytoplasmic tyrosine phosphatases that possess two tandem SH2 domains. To investigate the biological functions of Shp-2, a targeted mutation has been introduced into the murine Shp-2 gene, which results in an internal deletion of residues 46-110 in the N-terminal SH2 domain. Shp-2 is required for embryonic development, as mice homozygous for the mutant allele die in utero at mid-gestation. The Shp-2 mutant embryos fail to gastrulate properly as evidenced by defects in the node, notochord and posterior elongation. Biochemical analysis of mutant cells indicates that Shp-2 can function as either a positive or negative regulator of MAP kinase activation, depending on the specific receptor pathway stimulated. In particular, Shp-2 is required for full and sustained activation of the MAP kinase pathway following stimulation with fibroblast growth factor (FGF), raising the possibility that the phenotype of Shp-2 mutant embryos results from a defect in FGF-receptor signalling. Thus, Shp-2 modulates tyrosine kinase signalling in vivo and is crucial for gastrulation during mammalian development.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Body Patterning / genetics*
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Calcium-Calmodulin-Dependent Protein Kinases / metabolism
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Endothelium, Vascular / embryology
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Endothelium, Vascular / enzymology
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Enzyme Activation / genetics
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Fibroblast Growth Factors / pharmacology
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Gastrula / enzymology
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Genes, Lethal
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Intracellular Signaling Peptides and Proteins
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Mesoderm / enzymology*
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Mice
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Mutation
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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 / metabolism
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Receptor Protein-Tyrosine Kinases / metabolism
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Receptors, Platelet-Derived Growth Factor / metabolism
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SH2 Domain-Containing Protein Tyrosine Phosphatases
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Signal Transduction / genetics
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src Homology Domains*
Substances
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Intracellular Signaling Peptides and Proteins
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Fibroblast Growth Factors
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Receptor Protein-Tyrosine Kinases
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Receptors, Platelet-Derived Growth Factor
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Calcium-Calmodulin-Dependent Protein Kinases
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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