I. Warshawsky et al., THE LOW-DENSITY-LIPOPROTEIN RECEPTOR-RELATED PROTEIN MEDIATES THE CELLULAR DEGRADATION OF TISSUE FACTOR PATHWAY INHIBITOR, Proceedings of the National Academy of Sciences of the United Statesof America, 91(14), 1994, pp. 6664-6668
The low density lipoprotein receptor-related protein/alpha(2)-macroglo
bulin receptor (LRP) is a cell-surface glycoprotein of 4525 amino acid
s that functions as a hepatic endocytosis receptor for several plasma
proteins. These include alpha(2)-macroglobulin-protease complexes, fre
e plasminogen activators as well as plasminogen activators complexed w
ith their inhibitors, and beta-migrating very low density lipoproteins
complexed with either apolipoprotein E or lipoprotein lipase. In the
current study we used human and rat hepatoma cell lines to demonstrate
that LRP can mediate the degradation of tissue factor pathway inhibit
or (TFPI), a Kunitz-type plasma serine protease inhibitor that regulat
es tissue factor-induced blood coagulation. The cellular degradation o
f I-125-labeled TFPI (I-125-TFPI) was inhibited more than 80% both by
antibodies directed against LRP and by the LRP-associated 39-kDa prote
in, a protein that inhibits the binding and/or cell-mediated degradati
on of all ligands by LRP. Using rat hepatoma cells, we report that at
4 degrees C, I-125-TFPI binds to approximately 2 x 10(6) sites per cel
l with an equilibrium dissociation constant of approximate to 30 nM. I
-125-TFPI binding to the cell surface is not inhibited by the 39-kDa p
rotein. Taken together, our results suggest that TFPI binds to an as-y
et-unidentified cell surface molecule. After binding, LRP mediates the
cellular degradation of TFPI.