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• W1990303944 abstract "The very low density lipoprotein (VLDL) receptor binds apolipoprotein E-rich lipoproteins as well as the 39-kDa receptor-associated protein (RAP). Ligand blotting experiments using RAP and immunoblotting experiments using an anti-VLDL receptor IgG detected the VLDL receptor in detergent extracts of human aortic endothelial cells, human umbilical vein endothelial cells, and human aortic smooth muscle cells. To gain insight into the role of the VLDL receptor in the vascular endothelium, its ligand binding properties were further characterized. In vitro binding experiments documented that lipoprotein lipase (LpL), a key enzyme in lipoprotein catabolism, binds with high affinity to purified VLDL receptor. In addition, urokinase complexed with plasminogen activator-inhibitor type I (uPA•PAI-1) also bound to the purified VLDL receptor with high affinity. To assess the capacity of the VLDL receptor to mediate the cellular internalization of ligands, an adenoviral vector was used to introduce the VLDL receptor gene into a murine embryonic fibroblast cell line deficient in the VLDL receptor and the LDL receptor-related protein, another endocytic receptor known to bind LpL and uPA•PAI-1 complexes. Infected fibroblasts that express the VLDL receptor mediate the cellular internalization of 125I-labeled LpL and uPA•PAI-1 complexes, leading to their degradation. Non-infected fibroblasts or fibroblasts infected with the lacZ gene did not internalize these ligands. These studies confirm that the VLDL receptor binds to and mediates the catabolism of LpL and uPA•PAI-1 complexes. Thus, the VLDL receptor may play a unique role on the vascular endothelium in lipoprotein catabolism by regulating levels of LpL and in the regulation of fibrinolysis by facilitating the removal of urokinase complexed with its inhibitor. The very low density lipoprotein (VLDL) receptor binds apolipoprotein E-rich lipoproteins as well as the 39-kDa receptor-associated protein (RAP). Ligand blotting experiments using RAP and immunoblotting experiments using an anti-VLDL receptor IgG detected the VLDL receptor in detergent extracts of human aortic endothelial cells, human umbilical vein endothelial cells, and human aortic smooth muscle cells. To gain insight into the role of the VLDL receptor in the vascular endothelium, its ligand binding properties were further characterized. In vitro binding experiments documented that lipoprotein lipase (LpL), a key enzyme in lipoprotein catabolism, binds with high affinity to purified VLDL receptor. In addition, urokinase complexed with plasminogen activator-inhibitor type I (uPA•PAI-1) also bound to the purified VLDL receptor with high affinity. To assess the capacity of the VLDL receptor to mediate the cellular internalization of ligands, an adenoviral vector was used to introduce the VLDL receptor gene into a murine embryonic fibroblast cell line deficient in the VLDL receptor and the LDL receptor-related protein, another endocytic receptor known to bind LpL and uPA•PAI-1 complexes. Infected fibroblasts that express the VLDL receptor mediate the cellular internalization of 125I-labeled LpL and uPA•PAI-1 complexes, leading to their degradation. Non-infected fibroblasts or fibroblasts infected with the lacZ gene did not internalize these ligands. These studies confirm that the VLDL receptor binds to and mediates the catabolism of LpL and uPA•PAI-1 complexes. Thus, the VLDL receptor may play a unique role on the vascular endothelium in lipoprotein catabolism by regulating levels of LpL and in the regulation of fibrinolysis by facilitating the removal of urokinase complexed with its inhibitor. INTRODUCTIONThe low density lipoprotein (LDL) 1The abbreviations used are: LDLlow density lipoproteinLRPlow density lipoprotein receptor-related proteinVLDLvery low density lipoproteinRAPreceptor-associated proteinapo Eapolipoprotein ELpLlipoprotein lipaseLpLCcarboxyl-terminal domain (residues 313-448) of lipoprotein lipaseuPAurokinasepro-uPApro-urokinasePAI-1plasminogen activator inhibitor type IAd-lacZadenovirus containing lacZ cDNAAd-VLDLRadenovirus containing VLDL receptor cDNAGSTglutathione S-transferasePAGEpolyacrylamide gel electrophoresisBSAbovine serum albuminuPARurokinase plasminogen activator receptor. receptor gene family includes the LDL receptor(1Yamamoto T. Davis G.C. Brown M.S. Schneider W.J. Casey M.L. Goldstein J.L. Russel D.W. Cell. 1984; 39: 27-38Abstract Full Text PDF PubMed Scopus (970) Google Scholar), the very low density lipoprotein (VLDL) receptor(2Takahashi S. Kawarabayasi Y. Nakai T. Sakai J. Yamamoto T. Proc. Natl. Acad. Sci. U. S. A. 1992; 89: 9252-9256Crossref PubMed Scopus (475) Google Scholar), the LDL receptor-related protein (LRP)(3Herz J. Hamann U. Rogne S. Myklebost O. Gausepohl H. Stanley K.K. EMBO J. 1988; 7: 4119-4127Crossref PubMed Scopus (736) Google Scholar), and glycoprotein 330(4Saito A. Pietromonaco S. Loo A.K.C. Farquhar M.G. Proc. Natl. Acad Sci. U. S. A. 1994; 91: 9725-9729Crossref PubMed Scopus (491) Google Scholar). Together, these molecules have important roles in the catabolism of lipoproteins, proteinases, proteinase-inhibitor complexes, and matrix proteins (for reviews, see (5Brown M.S. Goldstein J.L. Science. 1986; 232: 34-47Crossref PubMed Scopus (4304) Google Scholar, 6Strickland D.K. Kounnas M.Z. Argraves W.S. FASEB J. 1995; 9: 890-898Crossref PubMed Scopus (248) Google Scholar, 7Krieger M. Herz J. Annu. Rev. Biochem. 1994; 63: 601-637Crossref PubMed Scopus (1057) Google Scholar, 8Yamamoto T. Takahashi S. Sakai J. Kawarabayasi Y. Trends Cardiovasc. Med. 1993; 3: 144-148Crossref PubMed Scopus (41) Google Scholar)). The members of this receptor family share structural motifs including cysteine-rich epidermal growth factor-like repeats, cysteine-rich ligand binding repeats, repeats containing the tetrapeptide sequence tyrosine-tryptophan-threonine-aspartic acid, and an asparagine-proline-X-tyrosine sequence within the cytoplasmic tail, which is responsible for endocytic signaling in coated pits.The most recently identified member of this receptor family is the VLDL receptor(2Takahashi S. Kawarabayasi Y. Nakai T. Sakai J. Yamamoto T. Proc. Natl. Acad. Sci. U. S. A. 1992; 89: 9252-9256Crossref PubMed Scopus (475) Google Scholar), so named because it appeared to specifically bind VLDL, probably via interaction with apolipoprotein E (apo E). At present, however, the physiological role of the VLDL receptor is uncertain. This receptor is most abundant in skeletal muscle, heart, adipose tissue, and brain(9Gåfvels M.E. Caird M. Britt D. Jackson C.L. Patterson D. Strauss III, J.F. Somat. Cell Mol. Genet. 1993; 19: 557-569Crossref PubMed Scopus (75) Google Scholar, 10Sakai J. Hoshino A. Takahashi S. Miura Y. Ishii H. Suzuki H. Kawarabayasi Y. Yamamoto T. J. Biol. Chem. 1994; 269: 2173-2182Abstract Full Text PDF PubMed Google Scholar, 11Webb J.C. Sun X.-M. Patel D.D. McCarthy S.N. Knight B.L. Soutar A.K. J. Lipid Res. 1992; 33: 689-698Abstract Full Text PDF PubMed Google Scholar), tissues which metabolize fatty acids as an energy source. This fact, and the observation that the VLDL receptor recognizes apo E-containing lipoproteins, has led to the hypothesis that the VLDL receptor may play an important role in the delivery of triglyceride-rich lipoproteins to peripheral tissues(8Yamamoto T. Takahashi S. Sakai J. Kawarabayasi Y. Trends Cardiovasc. Med. 1993; 3: 144-148Crossref PubMed Scopus (41) Google Scholar). Interestingly, a number of tissues that express high levels of the VLDL receptor also express lipoprotein lipase (LpL)(12Kirchgessner T.G. LeBoeuf R.C. Langner C.A. Zollman S. Chang C.H. Taylor B.A. Schotz M.C. Gordon J.I. Lusis A.J. J. Biol. Chem. 1989; 264: 1473-1482Abstract Full Text PDF PubMed Google Scholar), a key enzyme in the metabolism of triglyceride-rich lipoproteins. It has been suggested that LpL may play an important role in conjunction with the VLDL receptor in the catabolism of lipoproteins(8Yamamoto T. Takahashi S. Sakai J. Kawarabayasi Y. Trends Cardiovasc. Med. 1993; 3: 144-148Crossref PubMed Scopus (41) Google Scholar).A chicken receptor has been identified that is responsible for the endocytosis of VLDL and vitellogenin(13Bujo H. Hermann M.O. Kaderli M. Jacobsen L. Surawara S. Yamamoto T. Schneider W.J. EMBO J. 1994; 13: 5165-5175Crossref PubMed Scopus (212) Google Scholar). The primary sequence of this receptor has a high degree of similarity with that of the mammalian VLDL receptors, indicating that it represents a chicken homologue. Insight into a function for the chicken VLDL receptor has been gained by identifying a mutant hen that is missing this receptor. Hens with this defect are characterized by hereditary hyperlipidemia and the absence of egg laying(14Nimpf J. Radosavljevic M.J. Schneider W.J. J. Biol. Chem. 1989; 264: 1393-1398Abstract Full Text PDF PubMed Google Scholar). These observations indicate that the chicken VLDL receptor plays a critical role in mediating the transport of triglycerides into growing oocytes.Recently, Battey et al.(15Battey F. Gåfvels M.E. Fitzgerald D.J. Argraves W.S. Chappell D.A. Strauss III, J.F. Strickland D.K. J. Biol. Chem. 1994; 269: 23268-23273Abstract Full Text PDF PubMed Google Scholar) discovered that a 39-kDa protein, termed the receptor-associated protein (RAP), binds with high affinity to the VLDL receptor and regulates its ligand binding properties. RAP was discovered when it copurified with LRP during ligand affinity chromatography(16Ashcom J.D. Tiller S.E. Dickerson K. Cravens J.L. Argraves W.S. Strickland D.K. J. Cell Biol. 1990; 110: 1041-1048Crossref PubMed Scopus (203) Google Scholar, 17Jensen P.H. Moestrup S.K. Gliemann J. FEBS Lett. 1989; 255: 275-280Crossref PubMed Scopus (72) Google Scholar). While the biological function of RAP remains unknown, it binds tightly to LRP, gp330, and the VLDL receptor and modulates their ligand binding activities(15Battey F. Gåfvels M.E. Fitzgerald D.J. Argraves W.S. Chappell D.A. Strauss III, J.F. Strickland D.K. J. Biol. Chem. 1994; 269: 23268-23273Abstract Full Text PDF PubMed Google Scholar, 18Herz J. Goldstein J.L. Strickland D.K. Ho Y.K. Brown M.S. J. Biol. Chem. 1991; 266: 21232-21238Abstract Full Text PDF PubMed Google Scholar, 19Williams S.E. Ashcom J.D. Argraves W.S. Strickland D.K. J. Biol. Chem. 1992; 267: 9035-9040Abstract Full Text PDF PubMed Google Scholar, 20Kounnas M.Z. Argraves W.S. Strickland D.K. J. Biol. Chem. 1992; 267: 21162-21166Abstract Full Text PDF PubMed Google Scholar). The localization of RAP within the endoplasmic reticulum (21Biemesderfer D. Dekan G. Aronson P.S. Farquhar M.G. Am. J. Physiol. 1993; 264: F1011-F1020PubMed Google Scholar) and studies in which the RAP gene was disrupted in mice (22Willnow T.E. Armstrong S.A. Hammer R.E. Herz J. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 4537-4541Crossref PubMed Scopus (246) Google Scholar) suggest that RAP may play an important role in the early processing of these receptors, perhaps in preventing association of the newly synthesized receptors with ligands or in regulating receptor transport or trafficking to the cell surface.The high affinity interaction between RAP and the VLDL receptor suggested that the VLDL receptor, like LRP and gp330, may interact with additional ligands, and the present studies were undertaken to more fully define the ligand binding characteristics of this newly discovered receptor. These studies demonstrate that the VLDL receptor is a multiligand receptor and may play an important role in lipoprotein catabolism, by binding and internalizing both VLDL and lipoprotein lipase, and in proteinase catabolism, by mediating the cellular uptake of urokinase (uPA) complexed to its inhibitor, plasminogen activator inhibitor type I (PAI-1).DISCUSSIONThe VLDL receptor is a newly discovered member of the LDL receptor family whose domain organization is remarkably similar to that of the LDL receptor, with the exception that the VLDL receptor contains an additional copy of a cysteine-rich ligand binding repeat. Despite similarities in the structure of these two receptors, a notable difference in their ligand binding properties exists. The LDL receptor binds and internalizes apo B-100 (LDL) or apo E-containing lipoproteins such as intermediate density lipoprotein, β-migrating VLDL, and VLDL (5Brown M.S. Goldstein J.L. Science. 1986; 232: 34-47Crossref PubMed Scopus (4304) Google Scholar). On the other hand, the VLDL receptor recognizes apo E-containing lipoproteins but only binds weakly to LDL(2Takahashi S. Kawarabayasi Y. Nakai T. Sakai J. Yamamoto T. Proc. Natl. Acad. Sci. U. S. A. 1992; 89: 9252-9256Crossref PubMed Scopus (475) Google Scholar). The differences in ligand binding properties of these two receptors were further highlighted when recent studies found that RAP binds with high affinity to the VLDL receptor (Kd = 0.7 nM) (15Battey F. Gåfvels M.E. Fitzgerald D.J. Argraves W.S. Chappell D.A. Strauss III, J.F. Strickland D.K. J. Biol. Chem. 1994; 269: 23268-23273Abstract Full Text PDF PubMed Google Scholar) but binds weakly to the LDL receptor (Kd = 300 nM)(36Medh J.D. Fry G.L. Bowen S.L. Pladet M.W. Strickland D.K. Chappell D.A. J. Biol. Chem. 1995; 270: 536-540Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar). Since the biological role of the VLDL receptor is not fully understood, the present investigation was initiated to gain insight into its function by further characterizing the ligand binding properties of this receptor.The strategy that was employed to measure the capacity of the VLDL receptor to mediate the cellular internalization of ligands involved introducing the VLDL receptor gene into a cell line deficient in this receptor and demonstrating an enhanced uptake of ligands in those cells expressing the VLDL receptor. A murine fibroblast cell line (26Willnow T.E. Herz J. J. Cell Sci. 1994; 107: 719-726Crossref PubMed Google Scholar) genetically deficient in LRP was utilized for this purpose. An adenoviral vector was chosen to introduce the gene for the VLDL receptor into these cells since adenovirus-mediated gene transfer to mammalian cells in culture has proven to be a highly effective means for introducing genes into a variety of cells(37Becker T.C. Noel R.J. Coats W.S. Gomez-Foix A.M. Alam T. Gerard R.D. Newgard C.B. Methods Cell Biol. 1994; 43: 161-189Crossref PubMed Scopus (561) Google Scholar). Immunoblotting and RAP ligand blotting experiments confirmed that infection of the PEA13 fibroblasts with Ad-VLDLR led to high levels of expression of this receptor.Using fibroblasts infected with Ad-VLDLR, we documented the ability of the VLDL receptor to mediate the cellular internalization and subsequent degradation of LpL. In this regard, the VLDL receptor is similar to other members of the LDL receptor family, such as LRP and gp330, both of which bind LpL and mediate its cellular catabolism(31Chappell D.A. Fry G.L. Waknitz M.A. Iverius P.-H. Williams S.E. Strickland D.K. J. Biol. Chem. 1992; 267: 25764-25767Abstract Full Text PDF PubMed Google Scholar, 38Kounnas M.Z. Chappell D.A. Strickland D.K. Argraves W.S. J. Biol. Chem. 1993; 268: 14176-14181Abstract Full Text PDF PubMed Google Scholar). Interestingly, Takahashi et al. (39Takahashi S. Suzuki J. Kohno M. Oida K. Tamai T. Miyabo S. Yamamoto T. Nakai T. J. Biol. Chem. 1995; 270: 15747-15754Abstract Full Text Full Text PDF PubMed Scopus (192) Google Scholar) recently demonstrated that both LpL and apo E enhance the binding of triglyceride-rich lipoproteins to the VLDL receptor, an effect that has also been noted on LRP-mediated uptake and degradation of triglyceride-rich lipoproteins(40Chappell D.A. Fry G.L. Waknitz M.A. Muhonen L.E. Pladet M.W. Iverius P.-H. Strickland D.K. J. Biol. Chem. 1993; 268: 14168-14175Abstract Full Text PDF PubMed Google Scholar). LpL is a key enzyme involved in lipoprotein metabolism and is synthesized by parenchymal cells, such as adipocytes(41Olivecrona T. Chernick S.S. Bengtsson-Olivecrona G. Garrison M. Scow R.O. J. Biol. Chem. 1987; 262: 10748-10759Abstract Full Text PDF PubMed Google Scholar). A significant portion of newly synthesized LpL appears to be degraded(42Cisar L. Hoogewerf A.J. Cupp M. Rapport C.A. Bensadoun A. J. Biol. Chem. 1989; 264: 1767-1774Abstract Full Text PDF PubMed Google Scholar), while the remainder is secreted and transferred by an unknown mechanism to nearby vascular endothelium, where it remains bound through interaction with membrane-associated heparan sulfate chains(43Bensadoun A. Annu. Rev. Nutr. 1991; 11: 217-237Crossref PubMed Scopus (102) Google Scholar, 44Stins M.F. Sivaram P. Sasaki A. Goldberg I.J. J. Lipid Res. 1993; 34: 1853-1861Abstract Full Text PDF PubMed Google Scholar). Triglyceride-rich lipoproteins bind transiently to LpL at the vascular endothelium, and the enzyme rapidly hydrolyzes triglycerides enabling tissues to utilize fatty acids from the lipoproteins, thereby transforming large lipoproteins, such as chylomicrons and VLDL into cholesterol-rich remnant lipoproteins, which can be taken up by the liver.In situ hybridization studies (34Multhaupt H.A.B. Jin H. Arenas-Elliot C. Strauss III, J.F. Gafvels M. Warhol M.J. McCrae K.P. Circulation. 1994; 90: 1-2Crossref PubMed Scopus (1) Google Scholar) have detected VLDL receptor mRNA in human endothelium. These results have been confirmed by Northern blot analysis (29Wittmaack F.M. Gafvels M.E. Bronner M. Matsuo H. McCrae K.R. Tomaszewski J.E. Robinson S.L. Strickland D.K. Strauss III, J.F. Endocrinology. 1995; 136: 340-348Crossref PubMed Scopus (96) Google Scholar) of mRNA isolated from human umbilical vein endothelial cells. The present studies used RAP ligand blotting and immunoblotting techniques on cell extracts to confirm that the VLDL receptor is expressed in human endothelial cells and smooth muscle cells. To assess the function of the VLDL receptor in mediating the internalization of ligands in human umbilical vein endothelial cells, 125I-labeled RAP was utilized as a ligand. These experiments revealed that the VLDL receptor appears to be functional in these cells since they rapidly internalize and degrade RAP. However, the role of the VLDL receptor in regulating levels of LpL on the endothelium at this time remains ambiguous, since variable results were obtained in our experiments. Possibly, this results from variable expression of the VLDL receptor in endothelial cells and the involvement of other cell surface molecules that bind LpL.In addition to its role in the catabolism of LpL and apoE-containing lipoproteins, the VLDL receptor may also play an important role in proteinase catabolism by binding and mediating the cellular internalization of uPA•PAI-1 complexes. uPA is synthesized by endothelial cells as a single chain zymogen, pro-uPA, that is converted to the active two chain enzyme (two chain-uPA) by proteolysis. The conversion of pro-uPA to active two chain-uPA is enhanced upon interaction with the urokinase plasminogen activator receptor (uPAR). This molecule is a 55-kDa glycosyl-phosphatidylinositol-anchored cell surface protein (45Roldan A.L. Cubellis M.V. Masucci M.T. Behrendt N. Lund L.R. Dano K. Appella E. Blasi F. EMBO J. 1990; 9: 467-474Crossref PubMed Scopus (539) Google Scholar, 46Ploug M. Ronne E. Behrendt N. Jensen A.L. Blasi F. Dano K. J. Biol. Chem. 1991; 266: 1926-1933Abstract Full Text PDF PubMed Google Scholar) that is localized on many cell types, including endothelial cells(47Haddock R.C. Spell M.L. Baker C.D. Grammer J.R. Parks J.M. Speidel M. Booyse F.M. J. Biol. Chem. 1991; 266: 21466-21473Abstract Full Text PDF PubMed Google Scholar). In addition to facilitating activation of pro-uPA, binding of u-PA to uPAR acts to localize uPA activity on the cell surface(48Ellis V. Dano K. Fibrinolysis. 1992; 6: 27-34Google Scholar), where it has been implicated in the process of pericellular proteolysis, cell migration, and tissue remodeling(49Blasi F. BioEssays. 1993; 15: 105-111Crossref PubMed Scopus (373) Google Scholar). uPA activity is regulated by PAI-1, a rapidly acting inhibitor that is also produced by the endothelium(50Schleef R.R. Loskutoff D.J. Haemostasis. 1988; 18: 328-341PubMed Google Scholar).Once a complex between uPA and PAI-1 forms, it is rapidly internalized and degraded in a process mediated by LRP(33Herz J. Clouthier D.E. Hammer R.E. Cell. 1992; 71: 411-421Abstract Full Text PDF PubMed Scopus (506) Google Scholar, 51Nykjaer A. Petersen C.M. Moller B. Jensen P.H. Moestrup S.K. Holtet T.L. Etzerodt M. Thogersen H.C. Munch M. Andreasen P.A. Gliemann J. J. Biol. Chem. 1992; 267: 14543-14546Abstract Full Text PDF PubMed Google Scholar). The results of the present investigation confirm that the VLDL receptor, like LRP, can also mediate the cellular catabolism of uPA•PAI-1 complexes. This conclusion is supported by in vitro binding studies, which document a high affinity interaction between uPA•PAI-1 complexes and the purified VLDL receptor. RAP was shown to antagonize the binding. Further, cultured fibroblasts expressing the VLDL receptor following infection with Ad-VLDLR mediate cellular uptake of 125I-labeled uPA•PAI-1 complexes leading to their degradation. Thus, the VLDL receptor, like LRP (51Nykjaer A. Petersen C.M. Moller B. Jensen P.H. Moestrup S.K. Holtet T.L. Etzerodt M. Thogersen H.C. Munch M. Andreasen P.A. Gliemann J. J. Biol. Chem. 1992; 267: 14543-14546Abstract Full Text PDF PubMed Google Scholar) and gp330 (52Moestrup S.K. Nielsen S. Andreasen P. Jorgensen K.E. Nykjaer A. Roigaard H. Gliemann J. Christensen E.I. J. Biol. Chem. 1993; 268: 16564-16570Abstract Full Text PDF PubMed Google Scholar), binds to uPA•PAI-1 complexes and mediates their cellular uptake and degradation. This conclusion is supported by recent findings of Heegaard et al.(53Heegaard C.W. Simonsen A.C.W. Oka K. Kjoller L. Christensen A. Madsen B. Ellgaard L. Chan L. Andreasen P.A. J. Biol. Chem. 1995; 270: 20855-20861Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar). The presence of the VLDL receptor on the vascular endothelium suggests a role for this receptor in regulating fibrinolysis, and our experiments suggest a major role for this receptor on the endothelium in regulating uPA•PAI-1 levels. However, it is apparent that other RAP-insensitive mechanisms exist on the vascular endothelium that contribute to the internalization of uPA•PAI-1 complexes.Both LRP and the VLDL receptor are able to mediate the cellular uptake of pro-uPA directly, although much less pro-uPA is internalized by either receptor when compared with uPA•PAI-1 complexes. This might relate to a decreased affinity of these receptors for pro-uPA when compared with uPA•PAI-1 complexes(28Kounnas M.Z. Henkin J. Argraves W.S. Strickland D.K. J. Biol. Chem. 1993; 268: 21862-21867Abstract Full Text PDF PubMed Google Scholar). Nykjaer et al.(54Nykjaer A. Kjoller L. Cohen R.L. Lawrence D.A. Garni-Wagner B.A. Todd III, R.F. van Zonneveld A. J. Biol. Chem. 1994; 269: 25668-25676Abstract Full Text PDF PubMed Google Scholar) found that soluble uPAR blocked the binding of pro-uPA to LRP, suggesting that uPAR may protect pro-uPA from LRP-mediated internalization. This observation may also extend to the VLDL receptor and stresses that a major function of uPAR is to protect uPA from being internalized and subsequently degraded.In summary, the present studies have found that the VLDL receptor, like other members of the LDL receptor family, is a multiligand receptor and, in addition to apo E-containing lipoproteins, also binds and mediates the cellular catabolism of LpL as well as uPA•PAI-1 complexes. The present studies detected the VLDL receptor in endothelial cells, and cell uptake experiments suggest that the VLDL receptor plays an important role, along with other molecules, in the regulation of uPA•PAI-1 levels on the vascular endothelium. INTRODUCTIONThe low density lipoprotein (LDL) 1The abbreviations used are: LDLlow density lipoproteinLRPlow density lipoprotein receptor-related proteinVLDLvery low density lipoproteinRAPreceptor-associated proteinapo Eapolipoprotein ELpLlipoprotein lipaseLpLCcarboxyl-terminal domain (residues 313-448) of lipoprotein lipaseuPAurokinasepro-uPApro-urokinasePAI-1plasminogen activator inhibitor type IAd-lacZadenovirus containing lacZ cDNAAd-VLDLRadenovirus containing VLDL receptor cDNAGSTglutathione S-transferasePAGEpolyacrylamide gel electrophoresisBSAbovine serum albuminuPARurokinase plasminogen activator receptor. receptor gene family includes the LDL receptor(1Yamamoto T. Davis G.C. Brown M.S. Schneider W.J. Casey M.L. Goldstein J.L. Russel D.W. Cell. 1984; 39: 27-38Abstract Full Text PDF PubMed Scopus (970) Google Scholar), the very low density lipoprotein (VLDL) receptor(2Takahashi S. Kawarabayasi Y. Nakai T. Sakai J. Yamamoto T. Proc. Natl. Acad. Sci. U. S. A. 1992; 89: 9252-9256Crossref PubMed Scopus (475) Google Scholar), the LDL receptor-related protein (LRP)(3Herz J. Hamann U. Rogne S. Myklebost O. Gausepohl H. Stanley K.K. EMBO J. 1988; 7: 4119-4127Crossref PubMed Scopus (736) Google Scholar), and glycoprotein 330(4Saito A. Pietromonaco S. Loo A.K.C. Farquhar M.G. Proc. Natl. Acad Sci. U. S. A. 1994; 91: 9725-9729Crossref PubMed Scopus (491) Google Scholar). Together, these molecules have important roles in the catabolism of lipoproteins, proteinases, proteinase-inhibitor complexes, and matrix proteins (for reviews, see (5Brown M.S. Goldstein J.L. Science. 1986; 232: 34-47Crossref PubMed Scopus (4304) Google Scholar, 6Strickland D.K. Kounnas M.Z. Argraves W.S. FASEB J. 1995; 9: 890-898Crossref PubMed Scopus (248) Google Scholar, 7Krieger M. Herz J. Annu. Rev. Biochem. 1994; 63: 601-637Crossref PubMed Scopus (1057) Google Scholar, 8Yamamoto T. Takahashi S. Sakai J. Kawarabayasi Y. Trends Cardiovasc. Med. 1993; 3: 144-148Crossref PubMed Scopus (41) Google Scholar)). The members of this receptor family share structural motifs including cysteine-rich epidermal growth factor-like repeats, cysteine-rich ligand binding repeats, repeats containing the tetrapeptide sequence tyrosine-tryptophan-threonine-aspartic acid, and an asparagine-proline-X-tyrosine sequence within the cytoplasmic tail, which is responsible for endocytic signaling in coated pits.The most recently identified member of this receptor family is the VLDL receptor(2Takahashi S. Kawarabayasi Y. Nakai T. Sakai J. Yamamoto T. Proc. Natl. Acad. Sci. U. S. A. 1992; 89: 9252-9256Crossref PubMed Scopus (475) Google Scholar), so named because it appeared to specifically bind VLDL, probably via interaction with apolipoprotein E (apo E). At present, however, the physiological role of the VLDL receptor is uncertain. This receptor is most abundant in skeletal muscle, heart, adipose tissue, and brain(9Gåfvels M.E. Caird M. Britt D. Jackson C.L. Patterson D. Strauss III, J.F. Somat. Cell Mol. Genet. 1993; 19: 557-569Crossref PubMed Scopus (75) Google Scholar, 10Sakai J. Hoshino A. Takahashi S. Miura Y. Ishii H. Suzuki H. Kawarabayasi Y. Yamamoto T. J. Biol. Chem. 1994; 269: 2173-2182Abstract Full Text PDF PubMed Google Scholar, 11Webb J.C. Sun X.-M. Patel D.D. McCarthy S.N. Knight B.L. Soutar A.K. J. Lipid Res. 1992; 33: 689-698Abstract Full Text PDF PubMed Google Scholar), tissues which metabolize fatty acids as an energy source. This fact, and the observation that the VLDL receptor recognizes apo E-containing lipoproteins, has led to the hypothesis that the VLDL receptor may play an important role in the delivery of triglyceride-rich lipoproteins to peripheral tissues(8Yamamoto T. Takahashi S. Sakai J. Kawarabayasi Y. Trends Cardiovasc. Med. 1993; 3: 144-148Crossref PubMed Scopus (41) Google Scholar). Interestingly, a number of tissues that express high levels of the VLDL receptor also express lipoprotein lipase (LpL)(12Kirchgessner T.G. LeBoeuf R.C. Langner C.A. Zollman S. Chang C.H. Taylor B.A. Schotz M.C. Gordon J.I. Lusis A.J. J. Biol. Chem. 1989; 264: 1473-1482Abstract Full Text PDF PubMed Google Scholar), a key enzyme in the metabolism of triglyceride-rich lipoproteins. It has been suggested that LpL may play an important role in conjunction with the VLDL receptor in the catabolism of lipoproteins(8Yamamoto T. Takahashi S. Sakai J. Kawarabayasi Y. Trends Cardiovasc. Med. 1993; 3: 144-148Crossref PubMed Scopus (41) Google Scholar).A chicken receptor has been identified that is responsible for the endocytosis of VLDL and vitellogenin(13Bujo H. Hermann M.O. Kaderli M. Jacobsen L. Surawara S. Yamamoto T. Schneider W.J. EMBO J. 1994; 13: 5165-5175Crossref PubMed Scopus (212) Google Scholar). The primary sequence of this receptor has a high degree of similarity with that of the mammalian VLDL receptors, indicating that it represents a chicken homologue. Insight into a function for the chicken VLDL receptor has been gained by identifying a mutant hen that is missing this receptor. Hens with this defect are characterized by hereditary hyperlipidemia and the absence of egg laying(14Nimpf J. Radosavljevic M.J. Schneider W.J. J. Biol. Chem. 1989; 264: 1393-1398Abstract Full Text PDF PubMed Google Scholar). These observations indicate that the chicken VLDL receptor plays a critical role in mediating the transport of triglycerides into growing oocytes.Recently, Battey et al.(15Battey F. Gåfvels M.E. Fitzgerald D.J. Argraves W.S. Chappell D.A. Strauss III, J.F. Strickland D.K. J. Biol. Chem. 1994; 269: 23268-23273Abstract Full Text PDF PubMed Google Scholar) discovered that a 39-kDa protein, termed the receptor-associated protein (RAP), binds with high affinity to the VLDL receptor and regulates its ligand binding properties. RAP was discovered when it copurified with LRP during ligand affinity chromatography(16Ashcom J.D. Tiller S.E. Dickerson K. Cravens J.L. Argraves W.S. Strickland D.K. J. Cell Biol. 1990; 110: 1041-1048Crossref PubMed Scopus (203) Google Scholar, 17Jensen P.H. Moestrup" @default.
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• W1990303944 title "The Very Low Density Lipoprotein Receptor Mediates the Cellular Catabolism of Lipoprotein Lipase and Urokinase-Plasminogen Activator Inhibitor Type I Complexes" @default.
• W1990303944 cites W1484985322 @default.
• W1990303944 cites W1486748575 @default.
• W1990303944 cites W1491650478 @default.
• W1990303944 cites W1495390974 @default.
• W1990303944 cites W152075184 @default.
• W1990303944 cites W1527704744 @default.
• W1990303944 cites W1528569669 @default.
• W1990303944 cites W1536899263 @default.
• W1990303944 cites W1539895365 @default.
• W1990303944 cites W1542242159 @default.
• W1990303944 cites W1546092720 @default.
• W1990303944 cites W1550247149 @default.
• W1990303944 cites W1565076288 @default.
• W1990303944 cites W1566481410 @default.
• W1990303944 cites W1571243395 @default.
• W1990303944 cites W1583346750 @default.
• W1990303944 cites W1600508667 @default.
• W1990303944 cites W1600667984 @default.
• W1990303944 cites W1606724950 @default.
• W1990303944 cites W1608303427 @default.
• W1990303944 cites W1611413521 @default.
• W1990303944 cites W1619700982 @default.
• W1990303944 cites W1627361141 @default.
• W1990303944 cites W1641240062 @default.
• W1990303944 cites W1853643611 @default.
• W1990303944 cites W1917724278 @default.
• W1990303944 cites W1917787915 @default.
• W1990303944 cites W1961817401 @default.
• W1990303944 cites W1963632483 @default.
• W1990303944 cites W1966596855 @default.
• W1990303944 cites W1995032745 @default.
• W1990303944 cites W1995618009 @default.
• W1990303944 cites W1999895486 @default.
• W1990303944 cites W2010715617 @default.
• W1990303944 cites W2026800576 @default.
• W1990303944 cites W2041398886 @default.
• W1990303944 cites W2059120300 @default.
• W1990303944 cites W2065880668 @default.
• W1990303944 cites W2072893670 @default.
• W1990303944 cites W2078923563 @default.
• W1990303944 cites W2084744450 @default.
• W1990303944 cites W2088738897 @default.
• W1990303944 cites W2094247513 @default.
• W1990303944 cites W2102910674 @default.
• W1990303944 cites W2118877270 @default.
• W1990303944 cites W2344994645 @default.
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