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. 1995 May 9;92(10):4537–4541. doi: 10.1073/pnas.92.10.4537

Functional expression of low density lipoprotein receptor-related protein is controlled by receptor-associated protein in vivo.

T E Willnow 1, S A Armstrong 1, R E Hammer 1, J Herz 1
PMCID: PMC41979  PMID: 7538675

Abstract

The 39-kDa receptor-associated protein (RAP) associates with the multifunctional low density lipoprotein (LDL) receptor-related protein (LRP) and thereby prevents the binding of all known ligands, including alpha 2-macroglobulin and chylomicron remnants. RAP is predominantly localized in the endoplasmic reticulum, raising the possibility that it functions as a chaperone or escort protein in the biosynthesis or intracellular transport of LRP. Here we have used gene targeting to show that RAP promotes the expression of functional LRP in vivo. The amount of mature, processed LRP is reduced in liver and brain of RAP-deficient mice. As a result, hepatic clearance of alpha 2-macroglobulin is impaired and remnant lipoproteins accumulate in the plasma of RAP-deficient mice that also lack functional LDL receptors. These results are consistent with the hypothesis that RAP stabilizes LRP within the secretory pathway. They also suggest a further mechanism by which the activity of an endocytic receptor may be modulated in vivo.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Armbrust E. V., Ferris P. J., Goodenough U. W. A mating type-linked gene cluster expressed in Chlamydomonas zygotes participates in the uniparental inheritance of the chloroplast genome. Cell. 1993 Sep 10;74(5):801–811. doi: 10.1016/0092-8674(93)90460-8. [DOI] [PubMed] [Google Scholar]
  2. Ashwell G., Harford J. Carbohydrate-specific receptors of the liver. Annu Rev Biochem. 1982;51:531–554. doi: 10.1146/annurev.bi.51.070182.002531. [DOI] [PubMed] [Google Scholar]
  3. Ball E. H., Singer S. J. Mitochondria are associated with microtubules and not with intermediate filaments in cultured fibroblasts. Proc Natl Acad Sci U S A. 1982 Jan;79(1):123–126. doi: 10.1073/pnas.79.1.123. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Battey F. D., Gåfvels M. E., FitzGerald D. J., Argraves W. S., Chappell D. A., Strauss J. F., 3rd, Strickland D. K. The 39-kDa receptor-associated protein regulates ligand binding by the very low density lipoprotein receptor. J Biol Chem. 1994 Sep 16;269(37):23268–23273. [PubMed] [Google Scholar]
  5. Beisiegel U., Weber W., Bengtsson-Olivecrona G. Lipoprotein lipase enhances the binding of chylomicrons to low density lipoprotein receptor-related protein. Proc Natl Acad Sci U S A. 1991 Oct 1;88(19):8342–8346. doi: 10.1073/pnas.88.19.8342. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Beisiegel U., Weber W., Ihrke G., Herz J., Stanley K. K. The LDL-receptor-related protein, LRP, is an apolipoprotein E-binding protein. Nature. 1989 Sep 14;341(6238):162–164. doi: 10.1038/341162a0. [DOI] [PubMed] [Google Scholar]
  7. Bermingham E., Lamb T., Avise J. C. Size polymorphism and heteroplasmy in the mitochondrial DNA of lower vertebrates. J Hered. 1986 Jul-Aug;77(4):249–252. doi: 10.1093/oxfordjournals.jhered.a110230. [DOI] [PubMed] [Google Scholar]
  8. Bibb M. J., Van Etten R. A., Wright C. T., Walberg M. W., Clayton D. A. Sequence and gene organization of mouse mitochondrial DNA. Cell. 1981 Oct;26(2 Pt 2):167–180. doi: 10.1016/0092-8674(81)90300-7. [DOI] [PubMed] [Google Scholar]
  9. Biemesderfer D., Dekan G., Aronson P. S., Farquhar M. G. Biosynthesis of the gp330/44-kDa Heymann nephritis antigenic complex: assembly takes place in the ER. Am J Physiol. 1993 Jun;264(6 Pt 2):F1011–F1020. doi: 10.1152/ajprenal.1993.264.6.F1011. [DOI] [PubMed] [Google Scholar]
  10. Birky C. W., Jr Transmission genetics of mitochondria and chloroplasts. Annu Rev Genet. 1978;12:471–512. doi: 10.1146/annurev.ge.12.120178.002351. [DOI] [PubMed] [Google Scholar]
  11. Bu G., Maksymovitch E. A., Geuze H., Schwartz A. L. Subcellular localization and endocytic function of low density lipoprotein receptor-related protein in human glioblastoma cells. J Biol Chem. 1994 Nov 25;269(47):29874–29882. [PubMed] [Google Scholar]
  12. Bu G., Williams S., Strickland D. K., Schwartz A. L. Low density lipoprotein receptor-related protein/alpha 2-macroglobulin receptor is an hepatic receptor for tissue-type plasminogen activator. Proc Natl Acad Sci U S A. 1992 Aug 15;89(16):7427–7431. doi: 10.1073/pnas.89.16.7427. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Cavallaro U., del Vecchio A., Lappi D. A., Soria M. R. A conjugate between human urokinase and saporin, a type-1 ribosome-inactivating protein, is selectively cytotoxic to urokinase receptor-expressing cells. J Biol Chem. 1993 Nov 5;268(31):23186–23190. [PubMed] [Google Scholar]
  14. Conese M., Olson D., Blasi F. Protease nexin-1-urokinase complexes are internalized and degraded through a mechanism that requires both urokinase receptor and alpha 2-macroglobulin receptor. J Biol Chem. 1994 Jul 8;269(27):17886–17892. [PubMed] [Google Scholar]
  15. Gyllensten U., Wharton D., Josefsson A., Wilson A. C. Paternal inheritance of mitochondrial DNA in mice. Nature. 1991 Jul 18;352(6332):255–257. doi: 10.1038/352255a0. [DOI] [PubMed] [Google Scholar]
  16. Gyllensten U., Wharton D., Wilson A. C. Maternal inheritance of mitochondrial DNA during backcrossing of two species of mice. J Hered. 1985 Sep-Oct;76(5):321–324. doi: 10.1093/oxfordjournals.jhered.a110103. [DOI] [PubMed] [Google Scholar]
  17. Hecht N. B., Liem H., Kleene K. C., Distel R. J., Ho S. M. Maternal inheritance of the mouse mitochondrial genome is not mediated by a loss or gross alteration of the paternal mitochondrial DNA or by methylation of the oocyte mitochondrial DNA. Dev Biol. 1984 Apr;102(2):452–461. doi: 10.1016/0012-1606(84)90210-0. [DOI] [PubMed] [Google Scholar]
  18. Herz J., Clouthier D. E., Hammer R. E. LDL receptor-related protein internalizes and degrades uPA-PAI-1 complexes and is essential for embryo implantation. Cell. 1992 Oct 30;71(3):411–421. doi: 10.1016/0092-8674(92)90511-a. [DOI] [PubMed] [Google Scholar]
  19. Herz J., Couthier D. E., Hammer R. E. Correction: LDL receptor-related protein internalizes and degrades uPA-PAI-1 complexes and is essential for embryo implantation. Cell. 1993 May 7;73(3):428–428. doi: 10.1016/0092-8674(93)90130-i. [DOI] [PubMed] [Google Scholar]
  20. Herz J., Goldstein J. L., Strickland D. K., Ho Y. K., Brown M. S. 39-kDa protein modulates binding of ligands to low density lipoprotein receptor-related protein/alpha 2-macroglobulin receptor. J Biol Chem. 1991 Nov 5;266(31):21232–21238. [PubMed] [Google Scholar]
  21. Herz J., Hamann U., Rogne S., Myklebost O., Gausepohl H., Stanley K. K. Surface location and high affinity for calcium of a 500-kd liver membrane protein closely related to the LDL-receptor suggest a physiological role as lipoprotein receptor. EMBO J. 1988 Dec 20;7(13):4119–4127. doi: 10.1002/j.1460-2075.1988.tb03306.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Hiraoka J., Hirao Y. Fate of sperm tail components after incorporation into the hamster egg. Gamete Res. 1988 Apr;19(4):369–380. doi: 10.1002/mrd.1120190408. [DOI] [PubMed] [Google Scholar]
  23. Hoeh W. R., Blakley K. H., Brown W. M. Heteroplasmy suggests limited biparental inheritance of Mytilus mitochondrial DNA. Science. 1991 Mar 22;251(5000):1488–1490. doi: 10.1126/science.1672472. [DOI] [PubMed] [Google Scholar]
  24. Hofer F., Gruenberger M., Kowalski H., Machat H., Huettinger M., Kuechler E., Blaas D. Members of the low density lipoprotein receptor family mediate cell entry of a minor-group common cold virus. Proc Natl Acad Sci U S A. 1994 Mar 1;91(5):1839–1842. doi: 10.1073/pnas.91.5.1839. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Hurst L. D., Hoekstra R. F. Evolutionary genetics. Shellfish genes kept in line. Nature. 1994 Apr 28;368(6474):811–812. doi: 10.1038/368811a0. [DOI] [PubMed] [Google Scholar]
  26. Ishibashi S., Brown M. S., Goldstein J. L., Gerard R. D., Hammer R. E., Herz J. Hypercholesterolemia in low density lipoprotein receptor knockout mice and its reversal by adenovirus-mediated gene delivery. J Clin Invest. 1993 Aug;92(2):883–893. doi: 10.1172/JCI116663. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Ji Z. S., Brecht W. J., Miranda R. D., Hussain M. M., Innerarity T. L., Mahley R. W. Role of heparan sulfate proteoglycans in the binding and uptake of apolipoprotein E-enriched remnant lipoproteins by cultured cells. J Biol Chem. 1993 May 15;268(14):10160–10167. [PubMed] [Google Scholar]
  28. Johnson L. V., Walsh M. L., Chen L. B. Localization of mitochondria in living cells with rhodamine 123. Proc Natl Acad Sci U S A. 1980 Feb;77(2):990–994. doi: 10.1073/pnas.77.2.990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Johnston P. A., Jahn R., Südhof T. C. Transmembrane topography and evolutionary conservation of synaptophysin. J Biol Chem. 1989 Jan 15;264(2):1268–1273. [PubMed] [Google Scholar]
  30. Kondo R., Satta Y., Matsuura E. T., Ishiwa H., Takahata N., Chigusa S. I. Incomplete maternal transmission of mitochondrial DNA in Drosophila. Genetics. 1990 Nov;126(3):657–663. doi: 10.1093/genetics/126.3.657. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Kounnas M. Z., Argraves W. S., Strickland D. K. The 39-kDa receptor-associated protein interacts with two members of the low density lipoprotein receptor family, alpha 2-macroglobulin receptor and glycoprotein 330. J Biol Chem. 1992 Oct 15;267(29):21162–21166. [PubMed] [Google Scholar]
  32. Kounnas M. Z., Henkin J., Argraves W. S., Strickland D. K. Low density lipoprotein receptor-related protein/alpha 2-macroglobulin receptor mediates cellular uptake of pro-urokinase. J Biol Chem. 1993 Oct 15;268(29):21862–21867. [PubMed] [Google Scholar]
  33. Kounnas M. Z., Morris R. E., Thompson M. R., FitzGerald D. J., Strickland D. K., Saelinger C. B. The alpha 2-macroglobulin receptor/low density lipoprotein receptor-related protein binds and internalizes Pseudomonas exotoxin A. J Biol Chem. 1992 Jun 25;267(18):12420–12423. [PubMed] [Google Scholar]
  34. Kowal R. C., Herz J., Goldstein J. L., Esser V., Brown M. S. Low density lipoprotein receptor-related protein mediates uptake of cholesteryl esters derived from apoprotein E-enriched lipoproteins. Proc Natl Acad Sci U S A. 1989 Aug;86(15):5810–5814. doi: 10.1073/pnas.86.15.5810. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Kowal R. C., Herz J., Weisgraber K. H., Mahley R. W., Brown M. S., Goldstein J. L. Opposing effects of apolipoproteins E and C on lipoprotein binding to low density lipoprotein receptor-related protein. J Biol Chem. 1990 Jun 25;265(18):10771–10779. [PubMed] [Google Scholar]
  36. Krieger M., Herz J. Structures and functions of multiligand lipoprotein receptors: macrophage scavenger receptors and LDL receptor-related protein (LRP). Annu Rev Biochem. 1994;63:601–637. doi: 10.1146/annurev.bi.63.070194.003125. [DOI] [PubMed] [Google Scholar]
  37. Kristensen T., Moestrup S. K., Gliemann J., Bendtsen L., Sand O., Sottrup-Jensen L. Evidence that the newly cloned low-density-lipoprotein receptor related protein (LRP) is the alpha 2-macroglobulin receptor. FEBS Lett. 1990 Dec 10;276(1-2):151–155. doi: 10.1016/0014-5793(90)80530-v. [DOI] [PubMed] [Google Scholar]
  38. Lamb T., Avise J. C. Directional introgression of mitochondrial DNA in a hybrid population of tree frogs: The influence of mating behavior. Proc Natl Acad Sci U S A. 1986 Apr;83(8):2526–2530. doi: 10.1073/pnas.83.8.2526. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Lansman R. A., Avise J. C., Huettel M. D. Critical experimental test of the possibility of "paternal leakage" of mitochondrial DNA. Proc Natl Acad Sci U S A. 1983 Apr;80(7):1969–1971. doi: 10.1073/pnas.80.7.1969. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Lindahl K. F., Hausmann B., Robinson P. J., Guénet J. L., Wharton D. C., Winking H. Mta, the maternally transmitted antigen, is determined jointly by the chromosomal Hmt and the extrachromosomal Mtf genes. J Exp Med. 1986 Feb 1;163(2):334–346. doi: 10.1084/jem.163.2.334. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Loveland B., Wang C. R., Yonekawa H., Hermel E., Lindahl K. F. Maternally transmitted histocompatibility antigen of mice: a hydrophobic peptide of a mitochondrially encoded protein. Cell. 1990 Mar 23;60(6):971–980. doi: 10.1016/0092-8674(90)90345-f. [DOI] [PubMed] [Google Scholar]
  42. Moestrup S. K., Gliemann J. Analysis of ligand recognition by the purified alpha 2-macroglobulin receptor (low density lipoprotein receptor-related protein). Evidence that high affinity of alpha 2-macroglobulin-proteinase complex is achieved by binding to adjacent receptors. J Biol Chem. 1991 Jul 25;266(21):14011–14017. [PubMed] [Google Scholar]
  43. Moestrup S. K., Gliemann J., Pallesen G. Distribution of the alpha 2-macroglobulin receptor/low density lipoprotein receptor-related protein in human tissues. Cell Tissue Res. 1992 Sep;269(3):375–382. doi: 10.1007/BF00353892. [DOI] [PubMed] [Google Scholar]
  44. Mokuno H., Brady S., Kotite L., Herz J., Havel R. J. Effect of the 39-kDa receptor-associated protein on the hepatic uptake and endocytosis of chylomicron remnants and low density lipoproteins in the rat. J Biol Chem. 1994 May 6;269(18):13238–13243. [PubMed] [Google Scholar]
  45. Nykjaer A., Petersen C. M., Møller B., Jensen P. H., Moestrup S. K., Holtet T. L., Etzerodt M., Thøgersen H. C., Munch M., Andreasen P. A. Purified alpha 2-macroglobulin receptor/LDL receptor-related protein binds urokinase.plasminogen activator inhibitor type-1 complex. Evidence that the alpha 2-macroglobulin receptor mediates cellular degradation of urokinase receptor-bound complexes. J Biol Chem. 1992 Jul 25;267(21):14543–14546. [PubMed] [Google Scholar]
  46. Orlando R. A., Kerjaschki D., Kurihara H., Biemesderfer D., Farquhar M. G. gp330 associates with a 44-kDa protein in the rat kidney to form the Heymann nephritis antigenic complex. Proc Natl Acad Sci U S A. 1992 Aug 1;89(15):6698–6702. doi: 10.1073/pnas.89.15.6698. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Orth K., Madison E. L., Gething M. J., Sambrook J. F., Herz J. Complexes of tissue-type plasminogen activator and its serpin inhibitor plasminogen-activator inhibitor type 1 are internalized by means of the low density lipoprotein receptor-related protein/alpha 2-macroglobulin receptor. Proc Natl Acad Sci U S A. 1992 Aug 15;89(16):7422–7426. doi: 10.1073/pnas.89.16.7422. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Pikó L., Matsumoto L. Number of mitochondria and some properties of mitochondrial DNA in the mouse egg. Dev Biol. 1976 Mar;49(1):1–10. doi: 10.1016/0012-1606(76)90253-0. [DOI] [PubMed] [Google Scholar]
  49. Soriano P., Montgomery C., Geske R., Bradley A. Targeted disruption of the c-src proto-oncogene leads to osteopetrosis in mice. Cell. 1991 Feb 22;64(4):693–702. doi: 10.1016/0092-8674(91)90499-o. [DOI] [PubMed] [Google Scholar]
  50. Strickland D. K., Ashcom J. D., Williams S., Battey F., Behre E., McTigue K., Battey J. F., Argraves W. S. Primary structure of alpha 2-macroglobulin receptor-associated protein. Human homologue of a Heymann nephritis antigen. J Biol Chem. 1991 Jul 15;266(20):13364–13369. [PubMed] [Google Scholar]
  51. Strickland D. K., Ashcom J. D., Williams S., Burgess W. H., Migliorini M., Argraves W. S. Sequence identity between the alpha 2-macroglobulin receptor and low density lipoprotein receptor-related protein suggests that this molecule is a multifunctional receptor. J Biol Chem. 1990 Oct 15;265(29):17401–17404. [PubMed] [Google Scholar]
  52. Viville S., Neefjes J., Lotteau V., Dierich A., Lemeur M., Ploegh H., Benoist C., Mathis D. Mice lacking the MHC class II-associated invariant chain. Cell. 1993 Feb 26;72(4):635–648. doi: 10.1016/0092-8674(93)90081-z. [DOI] [PubMed] [Google Scholar]
  53. Warshawsky I., Broze G. J., Jr, Schwartz A. L. The low density lipoprotein receptor-related protein mediates the cellular degradation of tissue factor pathway inhibitor. Proc Natl Acad Sci U S A. 1994 Jul 5;91(14):6664–6668. doi: 10.1073/pnas.91.14.6664. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Williams S. E., Ashcom J. D., Argraves W. S., Strickland D. K. A novel mechanism for controlling the activity of alpha 2-macroglobulin receptor/low density lipoprotein receptor-related protein. Multiple regulatory sites for 39-kDa receptor-associated protein. J Biol Chem. 1992 May 5;267(13):9035–9040. [PubMed] [Google Scholar]
  55. Willnow T. E., Goldstein J. L., Orth K., Brown M. S., Herz J. Low density lipoprotein receptor-related protein and gp330 bind similar ligands, including plasminogen activator-inhibitor complexes and lactoferrin, an inhibitor of chylomicron remnant clearance. J Biol Chem. 1992 Dec 25;267(36):26172–26180. [PubMed] [Google Scholar]
  56. Willnow T. E., Orth K., Herz J. Molecular dissection of ligand binding sites on the low density lipoprotein receptor-related protein. J Biol Chem. 1994 Jun 3;269(22):15827–15832. [PubMed] [Google Scholar]
  57. Willnow T. E., Sheng Z., Ishibashi S., Herz J. Inhibition of hepatic chylomicron remnant uptake by gene transfer of a receptor antagonist. Science. 1994 Jun 3;264(5164):1471–1474. doi: 10.1126/science.7515194. [DOI] [PubMed] [Google Scholar]
  58. Yonekawa H., Moriwaki K., Gotoh O., Miyashita N., Migita S., Bonhomme F., Hjorth J. P., Petras M. L., Tagashira Y. Origins of laboratory mice deduced from restriction patterns of mitochondrial DNA. Differentiation. 1982;22(3):222–226. doi: 10.1111/j.1432-0436.1982.tb01255.x. [DOI] [PubMed] [Google Scholar]
  59. Zheng G., Bachinsky D. R., Stamenkovic I., Strickland D. K., Brown D., Andres G., McCluskey R. T. Organ distribution in rats of two members of the low-density lipoprotein receptor gene family, gp330 and LRP/alpha 2MR, and the receptor-associated protein (RAP). J Histochem Cytochem. 1994 Apr;42(4):531–542. doi: 10.1177/42.4.7510321. [DOI] [PubMed] [Google Scholar]
  60. Zouros E., Freeman K. R., Ball A. O., Pogson G. H. Direct evidence for extensive paternal mitochondrial DNA inheritance in the marine mussel Mytilus. Nature. 1992 Oct 1;359(6394):412–414. doi: 10.1038/359412a0. [DOI] [PubMed] [Google Scholar]
  61. Zouros E., Oberhauser Ball A., Saavedra C., Freeman K. R. An unusual type of mitochondrial DNA inheritance in the blue mussel Mytilus. Proc Natl Acad Sci U S A. 1994 Aug 2;91(16):7463–7467. doi: 10.1073/pnas.91.16.7463. [DOI] [PMC free article] [PubMed] [Google Scholar]

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