Abstract
The tissue factor/coagulation factor VIIa (TF/FVIIa) complex induces transactivation of the IGF-1 receptor (IGF-1R) in a number of different cell types. The mechanism is largely unknown. The transactivation leads to protection from apoptosis and nuclear translocation of the IGF-1R. The aim of this study was to clarify the signaling pathway between TF and IGF-1R after FVIIa treatment with PC3 and DU145 prostate or MDA-MB-231 breast cancer cells as model systems. Protein interactions, levels, and phosphorylations were assessed by proximity ligation assay or flow cytometry in intact cells and by western blot on cell lysates. The transactivation of the IGF-1R was found dependent on TF/FVIIa-induced activation of β1-integrins. A series of experiments led to the conclusion that the caveolae protein caveolin-1 prevented IGF-1R activation in resting cells via its scaffolding domain. TF/FVIIa/β1-integrins terminated this inhibition by activation of Src family kinases and subsequent phosphorylation of caveolin-1 on tyrosine 14. This phosphorylation was not seen after treatment with PAR1 or PAR2 agonists. Consequently, the protective effect of FVIIa against apoptosis induced by the death receptor agonist TRAIL and the de novo synthesis of cyclin D1 induced by nuclear IGF-1R accumulation were both significantly reduced by down-regulation of β1-integrins or overexpression of the caveolin-1 scaffolding domain. In conclusion, we present a plausible mechanism for the interplay between TF and IGF-1R involving FVIIa, β1-integrins, Src family proteins, and caveolin-1. Our results increase the knowledge of diseases associated with TF and IGF-1R overexpression in general but specifically of TF-mediated signaling with focus on cell survival.
Highlights
Tissue factor (TF) is a 47 kDa transmembrane glycoprotein and the initiator of the humoral coagulation
The transactivation of IGF-1 receptor (IGF-1R) by TF/FVIIa was evaluated by PLA in situ in PC3 cells, and in PC3 cells treated with scramble and ITGβ1 siRNA (Fig. 1c)
No activation of the IGF-1R could be recorded in the ITGβ1 siRNA treated cells. These experiments indicate that FVIIa treatment increases the interplay between ITGβ1 and TF and that the subsequent activation of ITGβ1 is important for the TF/FVIIa-dependent transactivation of IGF-1R
Summary
Tissue factor (TF) is a 47 kDa transmembrane glycoprotein and the initiator of the humoral coagulation. TF binds and activates its natural ligand coagulation factor VII (FVII) into FVIIa, an event that leads to activation of factor Xa (FXa) and thrombin and subsequently fibrin formation. The reduction in caspase-3 activation was dependent on the proteolytic activity of FVIIa and the PI3kinase/AKT signaling pathway, but independent of FXa and thrombin. Serum depletion from the MDA-MB-231 cells activated caspase-8, the initiator caspase in the extrinsic pathway [18]. Similar to caspase-3, caspase-8 activation was sensitive to TF/FVIIa-dependent signaling. A rapid up-regulation of both caspase-8 and -3 was recorded after TRAIL-receptor activation in both MDA-MB-231 breast and PC3 prostate cancer cells which was reduced after treatment with FVIIa [18]
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