title: FVIIa:TF induces cell survival via G12/G13-dependent Jak/STAT activation and BclXL production.
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.
authors.affiliation: Laboratory of Experimental Internal Medicine, G2-131, Academic Medical Center, Meibergdreef 9, 1105AZ Amsterdam, The Netherlands. h.h.versteeg@amc.uva.nl
authors.forename: Henri H
authors.initials: HH
authors.lastname: Versteeg
authors.forename: C Arnold
authors.initials: CA
authors.lastname: Spek
authors.forename: Sjoukje H
authors.initials: SH
authors.lastname: Slofstra
authors.forename: Sander H
authors.initials: SH
authors.lastname: Diks
authors.forename: Dick J
authors.initials: DJ
authors.lastname: Richel
authors.forename: Maikel P
authors.initials: MP
authors.lastname: Peppelenbosch
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D002460:Cell Line / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D006224:Cricetinae; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005167:Factor VII / Q000037:antagonists & inhibitors / Q000235:genetics / Q000494:pharmacology*; D015942:Factor VIIa / Q000502:physiology; D044365:GTP-Binding Protein alpha Subunits, G12-G13 / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects; D006629:Hirudins / Q000494:pharmacology; D053614:Janus Kinase 2; D008647:Mesocricetus; D008894:Milk Proteins; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000502:physiology; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000502:physiology; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000494:pharmacology*; D050799:STAT5 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects*; D013917:Thrombin / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D013925:Thromboplastin / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology* / Q000502:physiology; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology; D015533:Transcriptional Activation; D014162:Transfection; D020032:Tyrphostins / Q000494:pharmacology; D051020:bcl-X Protein
chemical_list: D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D006629:Hirudins; D008894:Milk Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; D051020:bcl-X Protein; D005167:Factor VII; D013925:Thromboplastin; C103587:recombinant FVIIa; D011505:Protein-Tyrosine Kinases; D053614:Janus Kinase 2; D015942:Factor VIIa; D013917:Thrombin; D044365:GTP-Binding Protein alpha Subunits, G12-G13