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rdf:type |
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lifeskim:mentions |
umls-concept:C0033371,
umls-concept:C0040649,
umls-concept:C0040661,
umls-concept:C0169661,
umls-concept:C0205263,
umls-concept:C0205419,
umls-concept:C0656342,
umls-concept:C0851827,
umls-concept:C1334291,
umls-concept:C1335875,
umls-concept:C1512032,
umls-concept:C1701901,
umls-concept:C1705050,
umls-concept:C1705162,
umls-concept:C1710082,
umls-concept:C1879547
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pubmed:issue |
4
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pubmed:dateCreated |
1998-6-30
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pubmed:abstractText |
PRL plays a central role in the regulation of milk protein gene expression in mammary epithelial cells and in the growth and differentiation of lymphocytes. It confers its activity through binding to a specific transmembrane, class I hematopoietic receptor. Ligand binding leads to receptor dimerization and activation of the tyrosine kinase Jak (janus kinase) 2, associated with the membrane-proximal, intracellular domain of the receptor. Jak2 phosphorylates and activates Stat5, a member of the Stat (signal transducers and activators of transcription) family. PRL receptor also activates SHP-2, a cytosolic tyrosine phosphatase. We investigated the connection between these two signaling events and derived a dominant negative mutant of SHP-2 comprising the two SH2 domains [SHP-2(SH2)2]. An analogous variant of the SHP-1 phosphatase [SHP-1(SH2)2] was used as a control. The dominant negative mutant of SHP-2 was found to inhibit the induction of tyrosine phosphorylation and DNA-binding activity of m-Stat5a, m-Stat5b, and the carboxyl-terminal deletion variant m-Stat5adelta749, as well as the transactivation potential of m-Stat5a and m-Stat5b. The dominant negative mutant SHP-1(SH2)2 had no effect. The kinase activity of Jak2 is also dependent on a functional SHP-2 phosphatase. We propose that SHP-2 relieves an inhibitory tyrosine phosphorylation event in Jak2 required for Jak2 activity, Stat5 phosphorylation, and transcriptional induction.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Caseins,
http://linkedlifedata.com/resource/pubmed/chemical/DNA-Binding Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Intracellular Signaling Peptides...,
http://linkedlifedata.com/resource/pubmed/chemical/JAK2 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Janus Kinase 2,
http://linkedlifedata.com/resource/pubmed/chemical/Milk Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/PTPN11 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/PTPN6 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Prolactin,
http://linkedlifedata.com/resource/pubmed/chemical/Protein Tyrosine Phosphatase...,
http://linkedlifedata.com/resource/pubmed/chemical/Protein Tyrosine Phosphatase...,
http://linkedlifedata.com/resource/pubmed/chemical/Protein Tyrosine Phosphatases,
http://linkedlifedata.com/resource/pubmed/chemical/Protein-Tyrosine Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/Proto-Oncogene Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Prolactin,
http://linkedlifedata.com/resource/pubmed/chemical/STAT5 Transcription Factor,
http://linkedlifedata.com/resource/pubmed/chemical/STAT5A protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/STAT5B protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Trans-Activators,
http://linkedlifedata.com/resource/pubmed/chemical/Tumor Suppressor Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Tyrosine
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pubmed:status |
MEDLINE
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pubmed:month |
Apr
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pubmed:issn |
0888-8809
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:volume |
12
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
556-67
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pubmed:dateRevised |
2009-11-19
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pubmed:meshHeading |
pubmed-meshheading:9544991-Animals,
pubmed-meshheading:9544991-COS Cells,
pubmed-meshheading:9544991-Caseins,
pubmed-meshheading:9544991-DNA-Binding Proteins,
pubmed-meshheading:9544991-Enzyme Activation,
pubmed-meshheading:9544991-Genes, Dominant,
pubmed-meshheading:9544991-Humans,
pubmed-meshheading:9544991-Intracellular Signaling Peptides and Proteins,
pubmed-meshheading:9544991-Janus Kinase 2,
pubmed-meshheading:9544991-Jurkat Cells,
pubmed-meshheading:9544991-Milk Proteins,
pubmed-meshheading:9544991-Mutagenesis, Site-Directed,
pubmed-meshheading:9544991-Phosphorylation,
pubmed-meshheading:9544991-Prolactin,
pubmed-meshheading:9544991-Promoter Regions, Genetic,
pubmed-meshheading:9544991-Protein Tyrosine Phosphatase, Non-Receptor Type 11,
pubmed-meshheading:9544991-Protein Tyrosine Phosphatase, Non-Receptor Type 6,
pubmed-meshheading:9544991-Protein Tyrosine Phosphatases,
pubmed-meshheading:9544991-Protein-Tyrosine Kinases,
pubmed-meshheading:9544991-Proto-Oncogene Proteins,
pubmed-meshheading:9544991-Receptors, Prolactin,
pubmed-meshheading:9544991-STAT5 Transcription Factor,
pubmed-meshheading:9544991-Sequence Deletion,
pubmed-meshheading:9544991-Trans-Activators,
pubmed-meshheading:9544991-Transcription, Genetic,
pubmed-meshheading:9544991-Transcriptional Activation,
pubmed-meshheading:9544991-Tumor Suppressor Proteins,
pubmed-meshheading:9544991-Tyrosine
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pubmed:year |
1998
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pubmed:articleTitle |
Dominant negative variants of the SHP-2 tyrosine phosphatase inhibit prolactin activation of Jak2 (janus kinase 2) and induction of Stat5 (signal transducer and activator of transcription 5)-dependent transcription.
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pubmed:affiliation |
Institute for Experimental Cancer Research, Tumor Biology Center and Department of Biology, University of Freiburg, Germany.
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pubmed:publicationType |
Journal Article
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