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Factor VIIa regulates the level of cell-surface tissue factor through separate but cooperative mechanisms

Madkhali, Yahya; Rondon, Araci M.R.; Featherby, Sophie; Maraveyas, Anthony; Greenman, John; Ettelaie, Camille


Yahya Madkhali

Araci M.R. Rondon

Sophie Featherby


Procoagulant activity of tissue factor (TF) in response to injury or inflammation is accompanied with cellular signals which determine the fate of cells. However, to prevent excessive signalling, TF is rapidly dissipated through release into microvesicles, and/or endocytosis. To elu-cidate the mechanism by which TF signalling may become moderated on the surface of cells, the associations of TF, fVII/fVIIa, PAR2 and caveolin-1 on MDA-MB-231, BxPC-3 and 786-O cells were examined and compared to that in cells lacking either fVII/fVIIa or TF. Furthermore, the localisa-tion of labelled-recombinant TF with cholesterol-rich lipid rafts was explored on the surface of primary human blood dermal endothelial cells (HDBEC). Finally, by disrupting the caveolae on the surface of HDBEC, the outcome on TF-mediated signalling was examined. The association between TF and PAR2 was found to be dependent on the presence of fVIIa. Interestingly, the presence of TF was not pre-requisite for the association between fVII/fVIIa and PAR2 but was significantly enhanced by TF, which was also essential for the proliferative signal. Supplementation of HDBEC with exogenous TF resulted in early release of fVII/fVIIa from caveolae, followed by re-sequestration of TF-fVIIa. Addition of labelled-TF resulted in the accumulation within caveo-lin-1-containing cholesterol-rich regions and was also accompanied with the increased assimilation of cell-surface fVIIa. Disruption of the caveolae/rafts in HDBEC using MβCD enhanced the TF-mediated cellular signalling. Our data supports a hypothesis that cells respond to the exposure to TF by moderating the signalling activities as well as the procoagulant activity of TF, through incorporation into the caveolae/lipid rafts.


Madkhali, Y., Rondon, A. M., Featherby, S., Maraveyas, A., Greenman, J., & Ettelaie, C. (2021). Factor VIIa regulates the level of cell-surface tissue factor through separate but cooperative mechanisms. Cancers, 13(15), Article 3718.

Journal Article Type Article
Acceptance Date Jul 21, 2021
Online Publication Date Jul 23, 2021
Publication Date Aug 1, 2021
Deposit Date Aug 3, 2021
Publicly Available Date Aug 5, 2021
Journal Cancers
Electronic ISSN 2072-6694
Publisher MDPI
Peer Reviewed Peer Reviewed
Volume 13
Issue 15
Article Number 3718
Keywords Tissue factor; Factor VIIa; Protease-activated receptor-2; Caveolae; Cholesterol-rich microdomins; Cell signalling
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