Cytokeratin 18 Is Expressed on the Hepatocyte Plasma Membrane Surface and Interacts with Thrombin-Antithrombin Complexes

During experiments to identify putative hepatic receptors for thrombin-antithrombin (TAT) complexes, a 45-kDa protein was identified by ligand blotting. Following gel purification, amino acid sequencing revealed the 45-kDa TAT-binding polypeptide to be cytokeratin 18 (CK18). The presence of CK18 on the surface of intact rat hepatoma cells was demonstrated by binding of125I-anti-CK18 antibodies. Anti-CK18 antibodies reduced the binding and internalization of 125I-TAT by rat hepatoma cells. Immunocytochemical analysis, to determine the location of CK18 in vivo, revealed a periportal gradient of CK18 staining; with hepatocytes around the portal triads demonstrating striking pericellular staining. In addition, anti-CK18 IgG associated with perfused livers to a significantly greater extent than preimmune IgG. Taken together, these data provide evidence that CK18 is found on the extracellular surface of hepatocytes and could play a role in TAT removal. Finally, these data, in conjunction with recent reports of CK8 (Hembrough, T. A., Li, L., and Gonias, S. L. (1996)J. Biol. Chem. 271, 25684–25691) and CK1 cell membrane surface expression (Schmaier, A. H. (1997) Thromb. Hemostasis 78, 101–107), indicate a novel role for these proteins as putative cellular receptors or cofactors to cellular receptors. During experiments to identify putative hepatic receptors for thrombin-antithrombin (TAT) complexes, a 45-kDa protein was identified by ligand blotting. Following gel purification, amino acid sequencing revealed the 45-kDa TAT-binding polypeptide to be cytokeratin 18 (CK18). The presence of CK18 on the surface of intact rat hepatoma cells was demonstrated by binding of125I-anti-CK18 antibodies. Anti-CK18 antibodies reduced the binding and internalization of 125I-TAT by rat hepatoma cells. Immunocytochemical analysis, to determine the location of CK18 in vivo, revealed a periportal gradient of CK18 staining; with hepatocytes around the portal triads demonstrating striking pericellular staining. In addition, anti-CK18 IgG associated with perfused livers to a significantly greater extent than preimmune IgG. Taken together, these data provide evidence that CK18 is found on the extracellular surface of hepatocytes and could play a role in TAT removal. Finally, these data, in conjunction with recent reports of CK8 (Hembrough, T. A., Li, L., and Gonias, S. L. (1996)J. Biol. Chem. 271, 25684–25691) and CK1 cell membrane surface expression (Schmaier, A. H. (1997) Thromb. Hemostasis 78, 101–107), indicate a novel role for these proteins as putative cellular receptors or cofactors to cellular receptors. The generation and regulation of thrombin is of central importance in the maintenance of hemostasis (1Fenton II, J.W. Semin. Thromb. Hemostasis. 1988; 14: 234-240Crossref PubMed Scopus (177) Google Scholar). Antithrombin, the main physiological regulator of thrombin, is a 60-kDa glycoprotein synthesized by the liver and found in plasma at a concentration of 2–5 μm (2Rosenberg R.D. Damus P.S. J. Biol. Chem. 1973; 248: 6490-6505Abstract Full Text PDF PubMed Google Scholar). The importance of the regulation of thrombin by antithrombin is demonstrated by the fact that individuals with inherited antithrombin deficiency have an increased tendency to develop thrombosis (3Blajchman M.A. Austin R.C. Fernandez-Rachubinski F.F. Sheffield W.P. Blood. 1992; 80: 2159-2171Crossref PubMed Google Scholar, 4Sheffield W.P. Wu Y.I. Blajchman M.A. High K.A. Roberts H.R. Molecular Basis of Thrombosis and Hemostasis. Marcel Dekker, Inc., New York1995: 355-377Google Scholar) The inhibition of thrombin by antithrombin is catalyzed by heparin and related naturally occurring glycosaminoglycans. This property of heparin accounts for its widespread clinical use as an anticoagulant and antithrombotic agent (5Hirsh J. N. Engl. J. Med. 1991; 324: 1565-1574Crossref PubMed Scopus (1002) Google Scholar).Antithrombin is a member of the protein superfamily known as theserine proteinase inhibitors orserpins (6Hunt L.T. Dayhoff M.O. Biochem. Biophys. Res. Commun. 1982; 95: 866-871Google Scholar). The serpin family includes both inhibitory proteins, which inhibit their cognate proteases, and proteins with no known inhibitory function. In addition to antithrombin, the inhibitory serpins include: α-AC, 1The abbreviations used are: α-AC, α1-antichymotrypsin; α-PI, α1-proteinase inhibitor; uPA, urokinase plasminogen activator; PPACK,d-phenylalanyl-l-prolyl-l-arginine-chloromethylketone; CK1, CK8, and CK18, cytokeratins 1, 8, and 18; HCII, heparin cofactor II; IF, intermediate filament; LRP, low and plasminogen inhibitors and II; inhibitor; thrombin-antithrombin 1The abbreviations used are: α-AC, α1-antichymotrypsin; α-PI, α1-proteinase inhibitor; uPA, urokinase plasminogen activator; PPACK,d-phenylalanyl-l-prolyl-l-arginine-chloromethylketone; CK1, CK8, and CK18, cytokeratins 1, 8, and 18; HCII, heparin cofactor II; IF, intermediate filament; LRP, low and plasminogen inhibitors and II; inhibitor; thrombin-antithrombin α-PI, HCII, and Biol. PubMed Scopus Google Scholar). The inhibitory serpins inhibitors which inhibit the of a which both serpin and in a in the serpin that to be for binding to putative hepatic and which their the J. Med. Full Text PDF Scopus Google in have demonstrated that than the or serpin in J. Med. Full Text PDF Scopus Google and and Scholar). in in with of the presence of liver receptors for their removal. putative receptors have serpin receptors and to be for the of of the serpins antithrombin, α-PI, α-AC, or HCII, serpin to be for the of J. Med. Full Text PDF Scopus Google Scholar). hepatic with binding to that of serpin identified on and and S. A. PubMed Scopus Google Scholar, S. J. 1992; PubMed Scopus Google Scholar, A. S. A. J. Biol. Chem. Full Text PDF PubMed Google Scholar). of α-PI, and the was found to the for binding to the J. J. Biol. Chem. 1991; Full Text PDF PubMed Google Scholar). of to a hepatoma plasma cell membrane protein to in the of an of the the of membrane protein J. Biol. Chem. 1991; Full Text PDF PubMed Google Scholar). the low protein demonstrated to a of TAT J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). the urokinase plasminogen J. Biol. Chem. Full Text PDF PubMed Google Scholar, A. J. J. Biol. PubMed Scopus Google Scholar) and J. J. Biol. Chem. 1992; Full Text PDF PubMed Google Scholar, J. J. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, S. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar) have to In provide evidence that CK18 a TAT or a cofactor to a of the family of proteins that found in 1982; Full Text PDF PubMed Scopus Google Scholar, J. Biol. PubMed Scopus Google Scholar). to that the surface of the to the plasma membrane T. S. T. T. S. PubMed Scopus Google Scholar, H. PubMed Scopus Google Scholar). of a central which is by and in Biol. PubMed Scopus Google Scholar, J. Full Text PDF PubMed Google Scholar, Biochem. PubMed Scopus Google Scholar). cytokeratin proteins have identified in and and these main which and II, which to proteins, cytokeratins the presence of both and proteins to J. Biol. PubMed Scopus Google Scholar). of cytokeratin is in the with in the and the in these cytokeratins the importance of the in The in the and with the of that cytokeratins have cells in addition to the to J. Full Text PDF PubMed Google Scholar, Biochem. PubMed Scopus Google the that cytokeratins and proteins to the the a of have evidence that proteins on the surface of cells and as receptors for plasma cell surface to plasminogen and Biochem. Biol. PubMed Scopus Google Scholar, J.W. J.W. S. A. PubMed Scopus Google Scholar, J. 95: PubMed Scopus Google to PubMed Scopus Google to plasminogen K.A. J. J. Biol. Chem. Full Text PDF PubMed Google and with J.W. PubMed Scopus Google Scholar). to CK8 to be a for plasminogen and plasminogen J. II, J. Google Scholar, L. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google and CK1 demonstrated to be an cell for Thromb. PubMed Scopus Google Scholar). In the data cell and liver which the of CK18 as a TAT-binding protein on the to identify the putative for of TAT the During the of these CK18 was identified as a TAT-binding protein associated with the plasma of This was on the TAT-binding protein liver plasma to TAT-binding protein a to and the of the TAT-binding protein in a property of The physiological of TAT with CK18 is the inhibition of 125I-TAT binding to hepatoma cells by anti-CK18 the of anti-CK18 antibodies to inhibit 125I-TAT of CK18 on the surface of hepatoma cells in and the in of anti-CK18 antibodies with to with an of CK8 on the cell surface of and cells J. II, J. Google Scholar, L. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, R.D. 1991; PubMed Scopus Google Scholar). CK1 demonstrated to be on the cell surface of cells Thromb. PubMed Scopus Google Scholar). The cell surface for cytokeratins is by surface of cells T. J. 1991; Google Scholar). the cell surface of proteins is as by the of on the surface of and cells by J.W. J.W. S. A. PubMed Scopus Google Scholar, J. 95: PubMed Scopus Google of with cell surface membrane proteins these LRP, and these TAT to with and S. A. PubMed Scopus Google Scholar, A. S. A. J. Biol. Chem. Full Text PDF PubMed Google Scholar, J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). In the the of TAT for to be low to is to which indicate low TAT binding to S. A. PubMed Scopus Google Scholar, A. S. A. J. Biol. Chem. Full Text PDF PubMed Google as as J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). TAT binding to cells a H. T. Biochem. Biophys. Res. Commun. PubMed Scopus Google TAT binding to cells was found to have Thromb. Res. Full Text PDF PubMed Scopus Google Scholar). In the the use of the binding to liver plasma a of TAT binding by In of TAT found to the and TAT binding to cells to a S. A. PubMed Scopus Google Scholar, A. S. A. J. Biol. Chem. Full Text PDF PubMed Google and have both to with is evidence to that TAT with H. T. Biochem. Biophys. Res. Commun. PubMed Scopus Google Scholar) demonstrated that TAT to a the to the of the inhibit or binding to cells H. T. Biochem. Biophys. Res. Commun. PubMed Scopus Google Scholar, PubMed Google Scholar). in the for have to have no on binding to cells H. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google its low for to be the for TAT internalization in in J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). to be in the internalization of TAT and proteins the binding for In addition to TAT low for LRP, its binding to was used in binding J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). This binding is in with the known for TAT in have found no evidence for TAT binding to H. T. Biochem. Biophys. Res. Commun. PubMed Scopus Google Scholar). a was found to be a of internalization by LRP, was found to inhibit binding to the cell the that TAT could to a protein than J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). This is as and have to to the with J. Biol. Chem. Full Text PDF PubMed Google Scholar, A. J. J. Biol. PubMed Scopus Google evidence to CK18 and CK8 and CK18 have to be found in a with the and protein in the plasma of cells N. S. L. J. Biol. PubMed Scopus Google Scholar). an plasma membrane glycoprotein of was a of cell with CK18 Biochem. J. PubMed Scopus Google Scholar). This protein could the of LRP, as Finally, the experiments provide evidence of CK18 cell surface expression in vivo, provide an of expression with that for LRP, in that is in hepatocytes to the portal triads J. Biochem. J. PubMed Scopus Google Scholar). Taken together, these the that CK18 be the TAT-binding protein on to with in the of intermediate indicate the of these for the of the of the and to indicate the of the cytokeratins to their the of CK8 demonstrated to be on the surface of cells and to be for plasminogen binding L. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). CK8 demonstrated to the of plasminogen on the cell surface and in the of cells L. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, L. Biochem. J. PubMed Scopus Google Scholar). In addition, the of with CK8 and CK18 in their increased and of S. A. PubMed Scopus Google Scholar). This novel role for cytokeratins is by their as cell surface receptors J. II, J. Google Scholar, L. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google the role for CK18 in TAT the is in provide evidence for the TAT and CK18 as as the presence of CK18 on the surface of hepatic cells and hepatocytes in liver data the that cytokeratins cellular receptors at the cell CK18 be in the of as as with by the and of cytokeratins as demonstrated for CK8 for plasminogen binding L. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar) and CK1 for Thromb. PubMed Scopus Google Scholar). with the of evidence for surface expression of proteins, data indicate and for cytokeratins as putative cellular as cofactors of cellular receptors. The generation and regulation of thrombin is of central importance in the maintenance of hemostasis (1Fenton II, J.W. Semin. Thromb. Hemostasis. 1988; 14: 234-240Crossref PubMed Scopus (177) Google Scholar). Antithrombin, the main physiological regulator of thrombin, is a 60-kDa glycoprotein synthesized by the liver and found in plasma at a concentration of 2–5 μm (2Rosenberg R.D. Damus P.S. J. Biol. Chem. 1973; 248: 6490-6505Abstract Full Text PDF PubMed Google Scholar). The importance of the regulation of thrombin by antithrombin is demonstrated by the fact that individuals with inherited antithrombin deficiency have an increased tendency to develop thrombosis (3Blajchman M.A. Austin R.C. Fernandez-Rachubinski F.F. Sheffield W.P. Blood. 1992; 80: 2159-2171Crossref PubMed Google Scholar, 4Sheffield W.P. Wu Y.I. Blajchman M.A. High K.A. Roberts H.R. Molecular Basis of Thrombosis and Hemostasis. Marcel Dekker, Inc., New York1995: 355-377Google Scholar) The inhibition of thrombin by antithrombin is catalyzed by heparin and related naturally occurring glycosaminoglycans. This property of heparin accounts for its widespread clinical use as an anticoagulant and antithrombotic agent (5Hirsh J. N. Engl. J. Med. 1991; 324: 1565-1574Crossref PubMed Scopus (1002) Google Scholar). is a member of the protein superfamily known as theserine proteinase inhibitors orserpins (6Hunt L.T. Dayhoff M.O. Biochem. Biophys. Res. Commun. 1982; 95: 866-871Google Scholar). The serpin family includes both inhibitory proteins, which inhibit their cognate proteases, and proteins with no known inhibitory function. In addition to antithrombin, the inhibitory serpins include: α-AC, 1The abbreviations used are: α-AC, α1-antichymotrypsin; α-PI, α1-proteinase inhibitor; uPA, urokinase plasminogen activator; PPACK,d-phenylalanyl-l-prolyl-l-arginine-chloromethylketone; CK1, CK8, and CK18, cytokeratins 1, 8, and 18; HCII, heparin cofactor II; IF, intermediate filament; LRP, low and plasminogen inhibitors and II; inhibitor; thrombin-antithrombin 1The abbreviations used are: α-AC, α1-antichymotrypsin; α-PI, α1-proteinase inhibitor; uPA, urokinase plasminogen activator; PPACK,d-phenylalanyl-l-prolyl-l-arginine-chloromethylketone; CK1, CK8, and CK18, cytokeratins 1, 8, and 18; HCII, heparin cofactor II; IF, intermediate filament; LRP, low and plasminogen inhibitors and II; inhibitor; thrombin-antithrombin α-PI, HCII, and Biol. PubMed Scopus Google Scholar). The inhibitory serpins inhibitors which inhibit the of a which both serpin and in a in the serpin that to be for binding to putative hepatic and which their the J. Med. Full Text PDF Scopus Google Scholar). in have demonstrated that than the or serpin in J. Med. Full Text PDF Scopus Google and and Scholar). in in with of the presence of liver receptors for their removal. putative receptors have serpin receptors and to be for the of of the serpins antithrombin, α-PI, α-AC, or HCII, serpin to be for the of J. Med. Full Text PDF Scopus Google Scholar). hepatic with binding to that of serpin identified on and and S. A. PubMed Scopus Google Scholar, S. J. 1992; PubMed Scopus Google Scholar, A. S. A. J. Biol. Chem. Full Text PDF PubMed Google Scholar). of α-PI, and the was found to the for binding to the J. J. Biol. Chem. 1991; Full Text PDF PubMed Google Scholar). of to a hepatoma plasma cell membrane protein to in the of an of the the of membrane protein J. Biol. Chem. 1991; Full Text PDF PubMed Google Scholar). the low protein demonstrated to a of TAT J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). the urokinase plasminogen J. Biol. Chem. Full Text PDF PubMed Google Scholar, A. J. J. Biol. PubMed Scopus Google Scholar) and J. J. Biol. Chem. 1992; Full Text PDF PubMed Google Scholar, J. J. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, S. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar) have to In provide evidence that CK18 a TAT or a cofactor to a of the family of proteins that found in 1982; Full Text PDF PubMed Scopus Google Scholar, J. Biol. PubMed Scopus Google Scholar). to that the surface of the to the plasma membrane T. S. T. T. S. PubMed Scopus Google Scholar, H. PubMed Scopus Google Scholar). of a central which is by and in Biol. PubMed Scopus Google Scholar, J. Full Text PDF PubMed Google Scholar, Biochem. PubMed Scopus Google Scholar). cytokeratin proteins have identified in and and these main which and II, which to proteins, cytokeratins the presence of both and proteins to J. Biol. PubMed Scopus Google Scholar). of cytokeratin is in the with in the and the in these cytokeratins the importance of the in The in the and with the of that cytokeratins have cells in addition to the to J. Full Text PDF PubMed Google Scholar, Biochem. PubMed Scopus Google Scholar). the that cytokeratins and proteins to the the a of have evidence that proteins on the surface of cells and as receptors for plasma cell surface to plasminogen and Biochem. Biol. PubMed Scopus Google Scholar, J.W. J.W. S. A. PubMed Scopus Google Scholar, J. 95: PubMed Scopus Google to PubMed Scopus Google to plasminogen K.A. J. J. Biol. Chem. Full Text PDF PubMed Google and with J.W. PubMed Scopus Google Scholar). to CK8 to be a for plasminogen and plasminogen J. II, J. Google Scholar, L. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google and CK1 demonstrated to be an cell for Thromb. PubMed Scopus Google Scholar). In the data cell and liver which the of CK18 as a TAT-binding protein on the to identify the putative for of TAT the During the of these CK18 was identified as a TAT-binding protein associated with the plasma of This was on the TAT-binding protein liver plasma to TAT-binding protein a to and the of the TAT-binding protein in a property of The physiological of TAT with CK18 is the inhibition of 125I-TAT binding to hepatoma cells by anti-CK18 the of anti-CK18 antibodies to inhibit 125I-TAT of CK18 on the surface of hepatoma cells in and the in of anti-CK18 antibodies with to with an of CK8 on the cell surface of and cells J. II, J. Google Scholar, L. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, R.D. 1991; PubMed Scopus Google Scholar). CK1 demonstrated to be on the cell surface of cells Thromb. PubMed Scopus Google Scholar). The cell surface for cytokeratins is by surface of cells T. J. 1991; Google Scholar). the cell surface of proteins is as by the of on the surface of and cells by J.W. J.W. S. A. PubMed Scopus Google Scholar, J. 95: PubMed Scopus Google of with cell surface membrane proteins these LRP, and these TAT to with and S. A. PubMed Scopus Google Scholar, A. S. A. J. Biol. Chem. Full Text PDF PubMed Google Scholar, J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). In the the of TAT for to be low to is to which indicate low TAT binding to S. A. PubMed Scopus Google Scholar, A. S. A. J. Biol. Chem. Full Text PDF PubMed Google as as J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). TAT binding to cells a H. T. Biochem. Biophys. Res. Commun. PubMed Scopus Google TAT binding to cells was found to have Thromb. Res. Full Text PDF PubMed Scopus Google Scholar). In the the use of the binding to liver plasma a of TAT binding by In of TAT found to the and TAT binding to cells to a S. A. PubMed Scopus Google Scholar, A. S. A. J. Biol. Chem. Full Text PDF PubMed Google and have both to with is evidence to that TAT with H. T. Biochem. Biophys. Res. Commun. PubMed Scopus Google Scholar) demonstrated that TAT to a the to the of the inhibit or binding to cells H. T. Biochem. Biophys. Res. Commun. PubMed Scopus Google Scholar, PubMed Google Scholar). in the for have to have no on binding to cells H. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google its low for to be the for TAT internalization in in J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). to be in the internalization of TAT and proteins the binding for In addition to TAT low for LRP, its binding to was used in binding J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). This binding is in with the known for TAT in have found no evidence for TAT binding to H. T. Biochem. Biophys. Res. Commun. PubMed Scopus Google Scholar). a was found to be a of internalization by LRP, was found to inhibit binding to the cell the that TAT could to a protein than J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). This is as and have to to the with J. Biol. Chem. Full Text PDF PubMed Google Scholar, A. J. J. Biol. PubMed Scopus Google evidence to CK18 and CK8 and CK18 have to be found in a with the and protein in the plasma of cells N. S. L. J. Biol. PubMed Scopus Google Scholar). an plasma membrane glycoprotein of was a of cell with CK18 Biochem. J. PubMed Scopus Google Scholar). This protein could the of LRP, as Finally, the experiments provide evidence of CK18 cell surface expression in vivo, provide an of expression with that for LRP, in that is in hepatocytes to the portal triads J. Biochem. J. PubMed Scopus Google Scholar). Taken together, these the that CK18 be the TAT-binding protein on to with in the of intermediate indicate the of these for the of the of the and to indicate the of the cytokeratins to their the of CK8 demonstrated to be on the surface of cells and to be for plasminogen binding L. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). CK8 demonstrated to the of plasminogen on the cell surface and in the of cells L. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, L. Biochem. J. PubMed Scopus Google Scholar). In addition, the of with CK8 and CK18 in their increased and of S. A. PubMed Scopus Google Scholar). This novel role for cytokeratins is by their as cell surface receptors J. II, J. Google Scholar, L. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google the role for CK18 in TAT the is in provide evidence for the TAT and CK18 as as the presence of CK18 on the surface of hepatic cells and hepatocytes in liver data the that cytokeratins cellular receptors at the cell CK18 be in the of as as with by the and of cytokeratins as demonstrated for CK8 for plasminogen binding L. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar) and CK1 for Thromb. PubMed Scopus Google Scholar). with the of evidence for surface expression of proteins, data indicate and for cytokeratins as putative cellular as cofactors of cellular receptors. The to identify the putative for of TAT the During the of these CK18 was identified as a TAT-binding protein associated with the plasma of This was on the TAT-binding protein liver plasma to TAT-binding protein a to and the of the TAT-binding protein in a property of The physiological of TAT with CK18 is the inhibition of 125I-TAT binding to hepatoma cells by anti-CK18 the of anti-CK18 antibodies to inhibit 125I-TAT of CK18 on the surface of hepatoma cells in and the in of anti-CK18 antibodies with to with an of CK8 on the cell surface of and cells J. II, J. Google Scholar, L. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, R.D. 1991; PubMed Scopus Google Scholar). CK1 demonstrated to be on the cell surface of cells Thromb. PubMed Scopus Google Scholar). The cell surface for cytokeratins is by surface of cells T. J. 1991; Google Scholar). the cell surface of proteins is as by the of on the surface of and cells by J.W. J.W. S. A. PubMed Scopus Google Scholar, J. 95: PubMed Scopus Google Scholar). The of with cell surface membrane proteins these LRP, and these TAT to with and S. A. PubMed Scopus Google Scholar, A. S. A. J. Biol. Chem. Full Text PDF PubMed Google Scholar, J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). In the the of TAT for to be low to is to which indicate low TAT binding to S. A. PubMed Scopus Google Scholar, A. S. A. J. Biol. Chem. Full Text PDF PubMed Google as as J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). TAT binding to cells a H. T. Biochem. Biophys. Res. Commun. PubMed Scopus Google TAT binding to cells was found to have Thromb. Res. Full Text PDF PubMed Scopus Google Scholar). In the the use of the binding to liver plasma a of TAT binding by In of TAT found to the and TAT binding to cells to a S. A. PubMed Scopus Google Scholar, A. S. A. J. Biol. Chem. Full Text PDF PubMed Google Scholar). and have both to with is evidence to that TAT with H. T. Biochem. Biophys. Res. Commun. PubMed Scopus Google Scholar) demonstrated that TAT to a the to the of the inhibit or binding to cells H. T. Biochem. Biophys. Res. Commun. PubMed Scopus Google Scholar, PubMed Google Scholar). in the for have to have no on binding to cells H. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). its low for to be the for TAT internalization in in J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). to be in the internalization of TAT and proteins the binding for In addition to TAT low for LRP, its binding to was used in binding J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). This binding is in with the known for TAT in have found no evidence for TAT binding to H. T. Biochem. Biophys. Res. Commun. PubMed Scopus Google Scholar). a was found to be a of internalization by LRP, was found to inhibit binding to the cell the that TAT could to a protein than J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). This is as and have to to the with J. Biol. Chem. Full Text PDF PubMed Google Scholar, A. J. J. Biol. PubMed Scopus Google Scholar). evidence to CK18 and CK8 and CK18 have to be found in a with the and protein in the plasma of cells N. S. L. J. Biol. PubMed Scopus Google Scholar). an plasma membrane glycoprotein of was a of cell with CK18 Biochem. J. PubMed Scopus Google Scholar). This protein could the of LRP, as Finally, the experiments provide evidence of CK18 cell surface expression in vivo, provide an of expression with that for LRP, in that is in hepatocytes to the portal triads J. Biochem. J. PubMed Scopus Google Scholar). Taken together, these the that CK18 be the TAT-binding protein on to with High in the of intermediate indicate the of these for the of the of the and to indicate the of the cytokeratins to their the of CK8 demonstrated to be on the surface of cells and to be for plasminogen binding L. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). CK8 demonstrated to the of plasminogen on the cell surface and in the of cells L. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, L. Biochem. J. PubMed Scopus Google Scholar). In addition, the of with CK8 and CK18 in their increased and of S. A. PubMed Scopus Google Scholar). This novel role for cytokeratins is by their as cell surface receptors J. II, J. Google Scholar, L. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). the role for CK18 in TAT the is in provide evidence for the TAT and CK18 as as the presence of CK18 on the surface of hepatic cells and hepatocytes in liver data the that cytokeratins cellular receptors at the cell CK18 be in the of as as with by the and of cytokeratins as demonstrated for CK8 for plasminogen binding L. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar) and CK1 for Thromb. PubMed Scopus Google Scholar). with the of evidence for surface expression of proteins, data indicate and for cytokeratins as putative cellular as cofactors of cellular receptors. and for