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Mechanism of tissue factor activation on HL-60 cells
1Veterans Affairs Medical Center, Research Service (151), Minneapolis, MN 55417, USA.
Blood
|May 1, 1997
Summary
Calcium ionophore ionomycin activates latent tissue factor (TF) procoagulant activity (PCA) in HL-60 cells. This calmodulin-dependent activation involves structural changes in TF, enhancing substrate binding and PCA.
Area of Science:
- Biochemistry
- Cell Biology
- Hematology
Background:
- Tissue Factor (TF) procoagulant activity (PCA) is typically encrypted on intact HL-60 cells.
- Understanding TF activation mechanisms is crucial for hemostasis and thrombosis research.
Purpose of the Study:
- To investigate the mechanism of ionomycin-induced activation of latent TF PCA.
- To elucidate the role of calmodulin in TF activation.
Main Methods:
- HL-60 cells were treated with ionomycin, a calcium ionophore.
- Calmodulin inhibition was assessed using calmidazolium.
- TF-factor VIIa complex formation and inhibitor binding were analyzed.
- Surface protein cross-linking was performed using dithiobis(sulfosuccinimidylpropionate).
Main Results:
- Ionomycin induced a >100-fold increase in TF PCA within seconds.
- The ionomycin effect was blocked by calmidazolium, indicating calmodulin dependence.
- Ionomycin treatment altered TF structure, enhancing pseudosubstrate inhibitor binding and reactivity with sulfosuccinimidyl-6-(biotinamido)hexanoate.
- TF cross-linking into dimers was inhibited by ionomycin treatment.
Conclusions:
- TF activation is a calmodulin-dependent process.
- Ionomycin induces a conformational change in TF, exposing its substrate binding site.
- This structural change likely involves alterations in TF quaternary structure, leading to increased PCA.
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