Abstract
Activation of Lyn, a Src-related nonreceptor tyrosine kinase, in trophoblast cells is associated with trophoblast giant cell differentiation. The purpose of the present work was to use Lyn as a tool to identify signaling pathways regulating the endocrine differentiation of trophoblast cells. The Src homology 3 domain of Lyn was shown to display differentiation-dependent associations with other regulatory proteins, including phosphatidylinositol 3-kinase (PI3-K). PI3-K activation was dependent upon trophoblast giant cell differentiation. The downstream mediator of PI3-K, Akt/protein kinase B, also exhibited differentiation-dependent activation. Lyn is a potential regulator of the PI3-K/Akt signaling pathway, as are receptor tyrosine kinases. Protein tyrosine kinase profiling was used to identify two candidate regulators of the PI3-K/Akt pathway, fibroblast growth factor receptor-1 and Sky. At least part of the activation of Akt in differentiating trophoblast giant cells involves an autocrine growth arrest-specific-6-Sky signaling pathway. Inhibition of PI3-K activities via treatment with LY294002 disrupted Akt activation and interfered with the endocrine differentiation of trophoblast giant cells. In summary, activation of the PI3-K/Akt signaling pathway regulates the development of the differentiated trophoblast giant cell phenotype.
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 / drug effects
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Cell Division / physiology
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Chromones / pharmacology
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Endocrine System / metabolism
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Enzyme Inhibitors / pharmacology
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Female
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Fetal Proteins / metabolism
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Mice
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Morpholines / pharmacology
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Phosphatidylinositol 3-Kinases / metabolism*
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Phosphoinositide-3 Kinase Inhibitors
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Phosphorylation
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Protein Serine-Threonine Kinases*
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Proto-Oncogene Proteins / drug effects
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Proto-Oncogene Proteins / metabolism*
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Proto-Oncogene Proteins c-akt
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Rats
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Receptor Protein-Tyrosine Kinases / metabolism
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Receptor, Fibroblast Growth Factor, Type 1
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Receptors, Fibroblast Growth Factor / metabolism
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Signal Transduction
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Trophoblasts / cytology*
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Trophoblasts / drug effects
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Trophoblasts / metabolism*
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src Homology Domains
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src-Family Kinases / drug effects
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src-Family Kinases / genetics
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src-Family Kinases / metabolism*
Substances
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Chromones
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Enzyme Inhibitors
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Fetal Proteins
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Morpholines
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Phosphoinositide-3 Kinase Inhibitors
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Proto-Oncogene Proteins
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Receptors, Fibroblast Growth Factor
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2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
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Fgfr1 protein, mouse
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Fgfr1 protein, rat
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Receptor Protein-Tyrosine Kinases
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Receptor, Fibroblast Growth Factor, Type 1
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TYRO3 protein, human
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lyn protein-tyrosine kinase
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src-Family Kinases
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Akt1 protein, rat
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt