Identification of Novel Downstream Molecules of Tissue Factor Activation by Comparative Proteomic Analysis

Kask, Lena; Jorsback, Anneli; Winkvist, Maria; Alfredsson, Jenny; Ek, Bo; Bergquist, Jonas; Siegbahn, Agneta

doi:10.1021/pr4006298

Cited by 3 publications

(3 citation statements)

References 33 publications

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“…3 4 5 6 7 8 9 TF is capable of initiating cellular signals in cells expressing this protein, and also on exposure of recipient cells to exogenous TF-containing microvesicles. TF signaling can alter the cellular gene expression profile 10 11 and has been demonstrated to include fVIIa activity and protease-activated receptor-2 (PAR2) activation. 12 13 14 15 16 17 18 Furthermore, interaction with β-integrins has also been implicated in inducing cell proliferation.…”

Section: Introductionmentioning

confidence: 99%

The Ratio of Factor VIIa:Tissue Factor Content within Microvesicles Determines the Differential Influence on Endothelial Cells

Madkhali

Featherby

Collier

et al. 2019

TH Open

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Tissue factor (TF)-positive microvesicles from various sources can promote cellular proliferation or alternatively induce apoptosis, but the determining factors are unknown. In this study the hypothesis that the ratio of fVIIa:TF within microvesicles determines this outcome was examined. Microvesicles were isolated from HepG2, BxPC-3, 786-O, MDA-MB-231, and MCF-7 cell lines and microvesicle-associated fVIIa and TF antigen and activity levels were measured. Human coronary artery endothelial cells (HCAECs) were incubated with these purified microvesicles, or with combinations of fVIIa-recombinant TF, and cell proliferation/apoptosis was measured. Additionally, by expressing mCherry-PAR2 on HCAEC surface, PAR2 activation was quantified. Finally, the activation of PAR2 on HCAEC or the activities of TF and fVIIa in microvesicles were blocked prior to addition of microvesicles to cells. The purified microvesicles exhibited a range of fVIIa:TF ratios with HepG2 and 786-O cells having the highest (54:1) and lowest (10:1) ratios, respectively. The reversal from proapoptotic to proliferative was estimated to occur at a fVIIa:TF molar ratio of 15:1, but HCAEC could not be rescued at higher TF concentrations. The purified microvesicles induced HCAEC proliferation or apoptosis according to this ruling. Blocking PAR2 activation on HCAEC, or inhibiting fVIIa or TF-procoagulant function on microvesicles prevented the influence on HCAEC. Finally, incubation of HCAEC with recombinant TF resulted in increased surface exposure of fVII. The induction of cell proliferation or apoptosis by TF-positive microvesicles is dependent on the ratio of fVIIa:TF and involves the activation of PAR2. At lower TF concentrations, fVIIa can counteract the proapoptotic stimulus and induce proliferation.

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Section: Introductionmentioning

confidence: 99%

The Ratio of Factor VIIa:Tissue Factor Content within Microvesicles Determines the Differential Influence on Endothelial Cells

Madkhali

Featherby

Collier

et al. 2019

TH Open

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“…Protein-disulfide isomerase has also been implicated in regulation of TF activity by acting on the Cys 186 -Cys 209 disulfide bond (22) and we recently found in a two-dimensional DIGE proteomic study that the reductant thioredoxin was significantly up-regulated upon FVIIa binding to TF (40). .…”

Section: Tf/fviia Cleaves Ephb2 and Epha2mentioning

confidence: 97%

The Eph Tyrosine Kinase Receptors EphB2 and EphA2 Are Novel Proteolytic Substrates of Tissue Factor/Coagulation Factor VIIa

Eriksson

Ramström

Hörnaeus

et al. 2014

Journal of Biological Chemistry

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Background:The tissue factor/coagulation factor VIIa (TF/FVIIa) complex cleaves protease-activated receptor 2 (PAR2), but other non-coagulant substrates are not known. Results: Truncated isoforms of the tyrosine kinase receptors EphB2 and EphA2 were formed after FVIIa stimulation. Conclusion: EphB2 and EphA2 are identified as novel proteolytic substrates of TF/FVIIa. Significance: The results provide new insights into PAR2-independent functions of TF/FVIIa.

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“…The two-dimensional difference gel electrophoresis technique was applied on TF-expressing cells. 72 By this technique and mass spectrometry, we could identify 13 novel proteins that were significantly regulated by the TF/FVIIa complex. These proteins are involved in various processes such as metabolism, glycolysis, cell motility, survival, and protein synthesis.…”

Section: Gene Expression and Protein Induction By Tf/fviia Complexmentioning

confidence: 99%

Tissue Factor Noncoagulant Signaling: Mechanisms and Implications for Cell Migration and Apoptosis

Åberg

Eriksson

Siegbahn

2015

Semin Thromb Hemost

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Tissue factor (TF) is a 47-kDa transmembrane glycoprotein and the main initiator of the blood coagulation cascade. Binding to its ligand factor VIIa (FVIIa) also initiates noncoagulant signaling with broad biological implications. In this review, we discuss how TF interacts with other cell-surface proteins, which affect biological functions such as cell migration and cell survival. A vast number of publications have demonstrated the importance of TF-induced activation of protease-activated receptors, but recently published research has indicated a more complicated picture. As it has been discovered that TF interacts with integrins and receptor tyrosine kinases, novel signaling mechanisms for the TF/FVIIa complex have been presented. The knowledge of these new aspects of TF signaling may, for instance, facilitate the development of new treatment strategies for cancer and acute coronary syndromes, two examples of diseases characterized by aberrant TF expression and signaling.

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Identification of Novel Downstream Molecules of Tissue Factor Activation by Comparative Proteomic Analysis

Cited by 3 publications

References 33 publications

The Ratio of Factor VIIa:Tissue Factor Content within Microvesicles Determines the Differential Influence on Endothelial Cells

The Ratio of Factor VIIa:Tissue Factor Content within Microvesicles Determines the Differential Influence on Endothelial Cells

The Eph Tyrosine Kinase Receptors EphB2 and EphA2 Are Novel Proteolytic Substrates of Tissue Factor/Coagulation Factor VIIa

Tissue Factor Noncoagulant Signaling: Mechanisms and Implications for Cell Migration and Apoptosis

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