FVIIa:TF Induces Cell Survival via G 12 /G 13 -Dependent Jak/STAT Activation and Bcl XL 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.