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(Circulation Research. 2004;94:1032.)
© 2004 American Heart Association, Inc.

Molecular Medicine

FVIIa:TF Induces Cell Survival via G₁₂/G₁₃-Dependent Jak/STAT Activation and Bcl_XL Production

Henri H. Versteeg, C. Arnold Spek, Sjoukje H. Slofstra, Sander H. Diks, Dick J. Richel, Maikel P. Peppelenbosch

From the Laboratory of Experimental Internal Medicine (H.H.V., C.A.S., S.H.S., S.H.D., M.P.P.) and Department of Medical Oncology (H.H.V., D.J.R.), Academic Medical Center, Amsterdam, The Netherlands.

Correspondence to Henri H. Versteeg, Laboratory of Experimental Internal Medicine, G2-131, Academic Medical Center, Meibergdreef 9, 1105AZ Amsterdam, The Netherlands. E-mail h.h.versteeg{at}amc.uva.nl

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.

Key Words: inflammation • survival • coagulation • signal transduction

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