Abstract
Tissue factor (TF), apart from activating the extrinsic pathway of the blood coagulation, is a principal regulator of embryonic and oncogenic angiogenesis, inflammation, leukocyte reverse transmigration, and tumor progression. It has become clear that these events are mediated by intracellular signal transduction elicited by TF/factor VIIa (FVIIa) interaction, but the details of this signaling remain largely obscure. In this study, we show that FVIIa/TF-interaction produces STAT5 phosphorylation, STAT5 nuclear translocation and transactivation of a STAT5 reporter construct. FVIIa-dependent STAT5 activation was dependent on FVIIa proteolytic activity but not on generation of the downstream coagulation factors Xa and thrombin, nor on the TF cytoplasmic domain. FVIIa-induced STAT5 phosphorylation was dependent on functional G12/G13 class G proteins and Jak2 activity, but not Jak1 or Tyk2. Finally, we show that FVIIa leads to cell survival through a Jak2/STAT5-dependent production of the antiapoptotic STAT5 target Bcl(XL) as well as Jak2-dependent activation of the antiapoptotic protein PKB. In conclusion, our results show that FVIIa induces cell survival through STAT5-dependent Bcl(XL) production and Jak2-dependent activation of PKB. Finally, we demonstrated for the first time that TF/FVIIa-signal transduction is dependent on G12/G13 class G proteins.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Active Transport, Cell Nucleus
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Animals
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Cell Line / drug effects
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Cell Survival / drug effects
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Cricetinae
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / physiology
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Enzyme Inhibitors / pharmacology
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Factor VII / antagonists & inhibitors
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Factor VII / genetics
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Factor VII / pharmacology*
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Factor VIIa / physiology
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GTP-Binding Protein alpha Subunits, G12-G13 / physiology
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Gene Expression Regulation / drug effects
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Hirudins / pharmacology
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Janus Kinase 2
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Mesocricetus
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Milk Proteins*
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Phosphorylation / drug effects
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Protein Processing, Post-Translational / drug effects
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Protein-Tyrosine Kinases / genetics
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Protein-Tyrosine Kinases / physiology
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Proto-Oncogene Proteins c-bcl-2 / biosynthesis
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Proto-Oncogene Proteins c-bcl-2 / genetics
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Proto-Oncogene Proteins*
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Recombinant Fusion Proteins / physiology
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Recombinant Proteins / antagonists & inhibitors
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Recombinant Proteins / genetics
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Recombinant Proteins / pharmacology*
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STAT5 Transcription Factor
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Signal Transduction / drug effects*
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Thrombin / antagonists & inhibitors
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Thrombin / biosynthesis
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Thromboplastin / chemistry
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Thromboplastin / genetics
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Thromboplastin / pharmacology*
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Thromboplastin / physiology
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Trans-Activators / genetics
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Trans-Activators / physiology
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Transcriptional Activation
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Transfection
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Tyrphostins / pharmacology
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bcl-X Protein
Substances
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DNA-Binding Proteins
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Enzyme Inhibitors
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Hirudins
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Milk Proteins
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-bcl-2
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Recombinant Fusion Proteins
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Recombinant Proteins
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STAT5 Transcription Factor
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Trans-Activators
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Tyrphostins
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alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide
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bcl-X Protein
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Factor VII
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Thromboplastin
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recombinant FVIIa
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Protein-Tyrosine Kinases
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Janus Kinase 2
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Factor VIIa
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Thrombin
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GTP-Binding Protein alpha Subunits, G12-G13