A. Iakhiaev et al., Catabolism of factor VIIa bound to tissue factor in fibroblasts in the presence and absence of tissue factor pathway inhibitor, J BIOL CHEM, 274(52), 1999, pp. 36995-37003
Vascular injury leads to the exposure of blood to fibroblasts and smooth mu
scle cells within the vessel wall. These cells constitutively express tissu
e factor (TF), the cellular receptor for plasma clotting factor VIIa (FVIIa
). Formation of TF . FVIIa complexes on cell surfaces triggers the blood co
agulation cascade. In the present study, we have investigated the fate of T
F . FVIIa complexes formed on the cell surface of fibroblasts in the presen
ce and absence of plasma inhibitor, tissue factor pathway inhibitor (TFPI),
FVIIa bound to TF on the cell surface was internalized and degraded withou
t depleting the cell surface TF antigen and activity. TFPI significantly en
hanced the TF-specific internalization and degradation of FVIIa, TFPI-enhan
ced internalization and degradation of FVIIa requires the C-terminal domain
of TFPI and factor Xa, TFPI . Xa-mediated internalization of FVIIa was ass
ociated with the depletion of TF from the cell surface. A majority of the i
nternalized FVIIa was degraded, but a small portion of the internalized FVI
Ia recycles back to the cell surface as an intact protein. In addition to T
F, other cell surface components, such as low density lipoprotein receptor-
related protein (LRP) and heparan sulfates, are essential for TFPI . Xa-ind
uced internalization of FVIIa, Acidification of cytosol, which selectively
inhibits the endocytotic pathway via coated pits, inhibited TFPI . Xa-media
ted internalization but not the basal internalization of FVIIa, Overall, ou
r data support the concept that FVIIa bound to cell surface TF was endocyto
sed by two different pathways. FVIIa complexed with TF in the absence of th
e inhibitor was internalized via a LRP-independent and probably noncoated p
it pathway, whereas FVIIa complexed with TF along with the inhibitor was in
ternalized via LRP-dependent coated pit pathway.