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Blood, 15 March 2001, Vol. 97, No. 6, pp. 1712-1720
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Tissue factor-mediated endocytosis, recycling, and
degradation of factor VIIa by a clathrin-independent mechanism not
requiring the cytoplasmic domain of tissue factor
Carsten B. Hansen,
Charles Pyke,
Lars C. Petersen, and
L. Vijaya Mohan Rao
From the Department of Tissue Factor/Factor
VIIa (TF/VIIa) Research, Health Care Discovery, Novo Nordisk
A/S, Maalov, Denmark, and the Department of Biochemistry, the
University of Texas Health Center at Tyler, TX.
Endocytosis and recycling of coagulation factor VIIa (VIIa)
bound to tissue factor (TF) was investigated in baby hamster kidney (BHK) cells stably transfected with TF or TF derivatives. Cell surface
expression of TF on BHK cells was required for VIIa internalization and
degradation. Approximately 50% of cell surface-bound VIIa was
internalized in one hour, and a majority of the internalized VIIa was
degraded soon thereafter. Similar rates of VIIa internalization and
degradation were obtained with BHK cells transfected with a cytoplasmic
domain-deleted TF variant or with a substitution of serine for
cysteine at amino acid residue 245 (C245S). Endocytosis of VIIa bound
to TF was an active process. Acidification of the cytosol, known to
inhibit the internalization via clathrin-coated pits, did not affect
the internalization of VIIa. Furthermore, receptor-associated protein,
known to block binding of all established ligands to members of the
low-density lipoprotein receptor family, was without an effect on the
internalization of VIIa. Addition of tissue factor pathway
inhibitor/factor Xa complex did not affect the internalization rate
significantly. A substantial portion (20% to 25%) of internalized
VIIa was recycled back to the cell surface as an intact and functional
protein. Although the recycled VIIa constitutes to only approximately
10% of available cell surface TF/VIIa sites, it accounts for 65% of
the maximal activation of factor X by the cell surface TF/VIIa. In
summary, the present data provide evidence that TF-dependent
internalization of VIIa in kidney cells occurs through a
clathrin-independent mechanism and does not require the cytoplasmic
domain of TF.
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