Factor VIIa binding to tissue factor on cell surfaces not only triggers the
coagulation cascade but also induces various intracellular responses that
may contribute to many pathophysiological processes. Active site-inhibited
factor VIIa, similar to factor VIIa, binds to tissue factor on cell surface
s and subsequently gets internalized and degraded. At present, it is unknow
n whether factor VIIa and active site-inhibited factor VIIa undergo a simil
ar intracellular processing. The data presented herein show that although a
fraction of both the internalized factor VIIa and active site-inhibited fa
ctor VIIa recycle back to the cell surface, the amount of active site-inhib
ited factor VIIa recycled back to the cell surface was substantially higher
than that of factor VIIa. Furthermore, internalized factor VIIa and not ac
tive site-inhibited factor VIIa associates with nuclear fractions. Factor V
IIa associated with the nuclear fraction was intact and functionally active
. In contrast to factor VIIa, tissue factor is not found in the nuclear fra
ction. Additional studies show that the internalized factor VIIa specifical
ly associates with cytoskeletal proteins, actin, and tubulin. In summary, t
he present data reveal that despite the common pathway of tissue factor-med
iated processing, considerable differences exist in the trafficking of fact
or VIIa and active site-inhibited factor VIIa in fibroblasts.