Abstract
Steroid hormones have rapid nongenomic effects on cell-signaling pathways, but the receptor mechanisms responsible for this are not understood. We have identified a specific polyproline motif in the amino-terminal domain of conventional progesterone receptor (PR) that mediates direct progestin-dependent interaction of PR with SH3 domains of various cytoplasmic signaling molecules, including c-Src tyrosine kinases. Through this interaction, PR is a potent activator of Src kinases working by an SH3 domain displacement mechanism. By mutagenesis, we also show that rapid progestin-induced activation of Src and downstream MAP kinase in mammalian cells is dependent on PR-SH3 domain interaction, but not on the transcriptional activity of PR. Preliminary evidence for the biological significance of this PR signaling pathway through regulatory SH3 domains was shown with respect to an influence on progestin-induced growth arrest of breast epithelial cells and induction of Xenopus oocyte maturation.
Publication types
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Amino Acid Motifs
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Animals
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Breast Neoplasms
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CSK Tyrosine-Protein Kinase
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Cell Line
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Female
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Humans
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Immunoblotting
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Mitogen-Activated Protein Kinases / metabolism
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Models, Biological
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Mutagenesis, Site-Directed
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Oocytes / drug effects
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Oocytes / physiology
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Progesterone / pharmacology
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Progesterone Congeners / pharmacology
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Promegestone / pharmacology
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Protein-Tyrosine Kinases / genetics
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Protein-Tyrosine Kinases / metabolism*
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-hck
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Receptors, Progesterone / chemistry*
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Receptors, Progesterone / genetics
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Receptors, Progesterone / metabolism*
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / metabolism
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Signal Transduction*
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Transfection
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Two-Hybrid System Techniques
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Xenopus laevis / physiology
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src Homology Domains / physiology*
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src-Family Kinases
Substances
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Progesterone Congeners
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Proto-Oncogene Proteins
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Receptors, Progesterone
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Recombinant Fusion Proteins
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Progesterone
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Promegestone
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Protein-Tyrosine Kinases
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CSK Tyrosine-Protein Kinase
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HCK protein, human
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Proto-Oncogene Proteins c-hck
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src-Family Kinases
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CSK protein, human
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Mitogen-Activated Protein Kinases