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p21-activated Kinase-1 Signaling Regulates Transcription of Tissue Factor and Tissue Factor Pathway Inhibitor*

  • Beatriz Sánchez-Solana
    Affiliations
    Department of Biochemistry and Molecular Biology, School of Medicine and Health Sciences, George Washington University, Washington, D. C. 20037
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  • Mona Motwani
    Affiliations
    Department of Biochemistry and Molecular Biology, School of Medicine and Health Sciences, George Washington University, Washington, D. C. 20037
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  • Da-Qiang Li
    Affiliations
    Department of Biochemistry and Molecular Biology, School of Medicine and Health Sciences, George Washington University, Washington, D. C. 20037
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  • Jeyanthy Eswaran
    Affiliations
    McCormick Proteomic and Genomic Center, School of Medicine and Health Sciences, George Washington University, Washington, D. C. 20037
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  • Rakesh Kumar
    Correspondence
    To whom correspondence should be addressed
    Affiliations
    Department of Biochemistry and Molecular Biology, School of Medicine and Health Sciences, George Washington University, Washington, D. C. 20037
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  • Author Footnotes
    * This work was supported, in whole or in part, by National Institutes of Health Grant CA90970 (to R. K.). This work was also supported by the McCormick Proteomic and Genomic Center.
    This article contains supplemental Tables S1–S3.
    ♦ This article was selected as a Paper of the Week.
Open AccessPublished:October 04, 2012DOI:https://doi.org/10.1074/jbc.M112.404061
      Tissue factor (TF) is a cell-surface glycoprotein responsible for initiating the coagulation cascade. Besides its role in homeostasis, studies have shown the implication of TF in embryonic development, cancer-related events, and inflammation via coagulation-dependent and -independent (signaling) mechanisms. Tissue factor pathway inhibitor (TFPI) plays an important role in regulating TF-initiated blood coagulation. Therefore, transcriptional regulation of TF expression and its physiological inhibitor TFPI would allow us to understand the critical step that controls many different processes. From a gene profiling study aimed at identifying differentially regulated genes between wild-type (WT) and p21-activated kinase 1-null (PAK1-KO) mouse embryonic fibroblasts (MEFs), we found TF and TFPI are differentially expressed in the PAK1-KO MEFs in comparison with wild-type MEFs. Based on these findings, we further investigated in this study the transcriptional regulation of TF and TFPI by PAK1, a serine/threonine kinase. We found that the PAK1·c-Jun complex stimulates the transcription of TF and consequently its procoagulant activity. Moreover, PAK1 negatively regulates the expression of TFPI and additionally contributes to increased TF activity. For the first time, this study implicates PAK1 in coagulation processes, through its dual transcriptional regulation of TF and its inhibitor.

      Introduction

      Tissue factor (TF)
      The abbreviations used are: TF
      tissue factor
      TFPI
      tissue factor pathway inhibitor
      MEF
      mouse embryonic fibroblast
      qPCR
      quantitative PCR
      pNA
      para-nitroaniline
      F
      factor.
      (also known as F3, coagulation factor III, or thromboplastin), a 47-kDa transmembrane glycoprotein and the primary initiator of the coagulation cascade (
      • McVey J.H.
      Tissue factor pathway.
      ), plays a critical role in homeostasis and thrombosis (
      • Nemerson Y.
      Tissue factor and hemostasis.
      ). It functions as a high affinity receptor for the serine proteases factors VII and VIIa. The resulting TF FVIIa complex activates both factors IX and X (FIX and FX) leading to thrombin generation and fibrin formation (
      • McVey J.H.
      Tissue factor pathway.
      ). TF-induced coagulation is regulated by a specific inhibitor termed tissue factor pathway inhibitor (TFPI). The mechanism of inhibition by TFPI involves its binding first to factor Xa (FXa) and then to the FVIIa TF complex (
      • McVey J.H.
      Tissue factor pathway.
      ).
      In the last few years, it has become evident that TF is involved in various other (patho-) physiological processes apart from homeostasis, such as embryonic development, transmission of signals, promotion of cell migration, adhesion, tumor initiation, growth, and inflammation (
      • Versteeg H.H.
      • Ruf W.
      Emerging insights in tissue factor-dependent signaling events.
      ). Concomitantly, TFPI, the physiological inhibitor of TF, has also been widely implicated in the regulation of these nonhomeostatic functions of TF (
      • Bajaj M.S.
      • Birktoft J.J.
      • Steer S.A.
      • Bajaj S.P.
      Structure and biology of tissue factor pathway inhibitor.
      ). TF is essential for the normal embryonic development, and its absence could lead to a defective vessel development and embryonic death in mice (
      • Bugge T.H.
      • Xiao Q.
      • Kombrinck K.W.
      • Flick M.J.
      • Holmbäck K.
      • Danton M.J.
      • Colbert M.C.
      • Witte D.P.
      • Fujikawa K.
      • Davie E.W.
      • Degen J.L.
      Fatal embryonic bleeding events in mice lacking tissue factor, the cell-associated initiator of blood coagulation.
      ). The expression of TF is deregulated in many cancers, and this up-regulation is often linked with aggressive malignancies (
      • Contrino J.
      • Hair G.
      • Kreutzer D.L.
      • Rickles F.R.
      In situ detection of tissue factor in vascular endothelial cells. Correlation with the malignant phenotype of human breast disease.
      ) and increased tumor growth (
      • Ruf W.
      Tissue factor and PAR signaling in tumor progression.
      ). Moreover, expression of TF amplifies the inflammatory reaction in patients with sepsis (
      • Levi M.
      • ten Cate H.
      • Bauer K.A.
      • van der Poll T.
      • Edgington T.S.
      • Büller H.R.
      • van Deventer S.J.
      • Hack C.E.
      • ten Cate J.W.
      • Rosenberg R.D.
      Inhibition of endotoxin-induced activation of coagulation and fibrinolysis by pentoxifylline or by a monoclonal anti-tissue factor antibody in chimpanzees.
      ,
      • van der Poll T.
      • Büller H.R.
      • ten Cate H.
      • Wortel C.H.
      • Bauer K.A.
      • van Deventer S.J.
      • Hack C.E.
      • Sauerwein H.P.
      • Rosenberg R.D.
      • ten Cate J.W.
      Activation of coagulation after administration of tumor necrosis factor to normal subjects.
      ).
      TF contributes to pathologies by activation of the coagulation cascade (proteolysis-dependent signaling) as well as by coagulation-independent (proteolysis-independent) signaling events via the cytoplasmic domain of TF (
      • Versteeg H.H.
      • Ruf W.
      Emerging insights in tissue factor-dependent signaling events.
      ,
      • Pendurthi U.R.
      • Rao L.V.
      Factor VIIa/tissue factor-induced signaling. A link between clotting and disease.
      ). Thus, TF might not only function as the initiator of coagulation but also as a transmembrane signaling receptor that regulates angiogenesis, tumor growth, metastasis, and inflammation. Therefore, understanding the transcriptional regulation of TF expression and its inhibitor, TFPI, would appear to be a critical step in the control of many different processes.
      The PAKs are serine/threonine kinases that were originally identified as binding partners and downstream effectors of Cdc42 and Rac1 in actin reorganization and cell migration (
      • Manser E.
      • Leung T.
      • Salihuddin H.
      • Zhao Z.S.
      • Lim L.
      A brain serine/threonine protein kinase activated by Cdc42 and Rac1.
      ). PAK1, the best characterized member of the PAK family, is activated by the p21ras-related proteins Cdc42 and Rac1 (
      • Manser E.
      • Leung T.
      • Salihuddin H.
      • Zhao Z.S.
      • Lim L.
      A brain serine/threonine protein kinase activated by Cdc42 and Rac1.
      ) and also by a wide variety of extracellular signals (
      • Tsakiridis T.
      • Taha C.
      • Grinstein S.
      • Klip A.
      Insulin activates a p21-activated kinase in muscle cells via phosphatidylinositol 3-kinase.
      ) that promote PAK1's auto-phosphorylation and stimulation of its kinase activity (
      • Molli P.R.
      • Li D.Q.
      • Murray B.W.
      • Rayala S.K.
      • Kumar R.
      PAK signaling in oncogenesis.
      ). PAK1 kinase activity has been implicated in a wide variety of cellular processes, including cell motility, survival and proliferation, morphogenesis, cytoskeleton remodeling, and transcription (
      • Vadlamudi R.K.
      • Kumar R.
      p21-activated kinases in human cancer.
      ). In addition to its well characterized kinase activity, the PAK1 pathway also affects nuclear events in a profound manner (
      • Barnes C.J.
      • Vadlamudi R.K.
      • Mishra S.K.
      • Jacobson R.H.
      • Li F.
      • Kumar R.
      Functional inactivation of a transcriptional corepressor by a signaling kinase.
      ,
      • Bagrodia S.
      • Dérijard B.
      • Davis R.J.
      • Cerione R.A.
      Cdc42 and PAK-mediated signaling leads to Jun kinase and p38 mitogen-activated protein kinase activation.
      ,
      • Brown J.L.
      • Stowers L.
      • Baer M.
      • Trejo J.
      • Coughlin S.
      • Chant J.
      Human Ste20 homologue hPAK1 links GTPases to the JNK MAP kinase pathway.
      ) and also regulates the transcription of target gene chromatin (
      • Singh R.R.
      • Song C.
      • Yang Z.
      • Kumar R.
      Nuclear localization and chromatin targets of p21-activated kinase 1.
      ,
      • Li F.
      • Adam L.
      • Vadlamudi R.K.
      • Zhou H.
      • Sen S.
      • Chernoff J.
      • Mandal M.
      • Kumar R.
      p21-activated kinase 1 interacts with and phosphorylates histone H3 in breast cancer cells.
      ,
      • Balasenthil S.
      • Sahin A.A.
      • Barnes C.J.
      • Wang R.A.
      • Pestell R.G.
      • Vadlamudi R.K.
      • Kumar R.
      p21-activated kinase-1 signaling mediates cyclin D1 expression in mammary epithelial and cancer cells.
      ).
      During a previous gene profiling study that includes wild-type (WT) and knock-out PAK1 (PAK1-KO) mouse embryonic fibroblasts (MEFs), we identified TF and TFPI to be down- and up-regulated, respectively, in the PAK1-KO MEFs in comparison with its wild-type controls,
      R. Kumar, unpublished data.
      suggesting that PAK1 might regulate the expression of TF and TFPI. Given the involvement of TF and TFPI in several pathological and physiological events, this study was undertaken to investigate the genomic regulation of TF and TFPI by PAK1 signaling. To date, nothing is known about the regulation of TF expression by PAK1 in cancer cells. We discovered, for the first time, that PAK1 signaling stimulates and inhibits the transcription of TF and TFPI, respectively, and modulates the coagulation process.

      Acknowledgments

      We thank the members of our laboratory for insightful discussions.

      Author Profile

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