8em4

Structural highlights

Function

LRP2_MOUSE Multiligand endocytic receptor. Acts together with CUBN to mediate endocytosis of high-density lipoproteins (PubMed:10766831). Mediates receptor-mediated uptake of polybasic drugs such as aprotinin, aminoglycosides and polymyxin B (By similarity). In the kidney, mediates the tubular uptake and clearance of leptin (PubMed:22841573). Also mediates transport of leptin across the blood-brain barrier through endocytosis at the choroid plexus epithelium (By similarity). Endocytosis of leptin in neuronal cells is required for hypothalamic leptin signaling and leptin-mediated regulation of feeding and body weight (PubMed:24825475). Mediates endocytosis and subsequent lysosomal degradation of CST3 in kidney proximal tubule cells (PubMed:17462596). Mediates renal uptake of 25-hydroxyvitamin D3 in complex with the vitamin D3 transporter GC/DBP (PubMed:10052453). Mediates renal uptake of metallothionein-bound heavy metals (By similarity). Together with CUBN, mediates renal reabsorption of myoglobin (By similarity). Mediates renal uptake and subsequent lysosomal degradation of APOM (By similarity). Plays a role in kidney selenium homeostasis by mediating renal endocytosis of selenoprotein SEPP1 (PubMed:18174160). Mediates renal uptake of the antiapoptotic protein BIRC5/survivin which may be important for functional integrity of the kidney (PubMed:23825075). Mediates renal uptake of matrix metalloproteinase MMP2 in complex with metalloproteinase inhibitor TIMP1 (PubMed:28659595). Mediates endocytosis of Sonic hedgehog protein N-product (ShhN), the active product of SHH (By similarity). Also mediates ShhN transcytosis (By similarity). In the embryonic neuroepithelium, mediates endocytic uptake and degradation of BMP4, is required for correct SHH localization in the ventral neural tube and plays a role in patterning of the ventral telencephalon (PubMed:15623804). Required at the onset of neurulation to sequester SHH on the apical surface of neuroepithelial cells of the rostral diencephalon ventral midline and to control PTCH1-dependent uptake and intracellular trafficking of SHH (PubMed:22340494). During neurulation, required in neuroepithelial cells for uptake of folate bound to the folate receptor FOLR1 which is necessary for neural tube closure (PubMed:24639464). In the adult brain, negatively regulates BMP signaling in the subependymal zone which enables neurogenesis to proceed (PubMed:20460439). In astrocytes, mediates endocytosis of ALB which is required for the synthesis of the neurotrophic factor oleic acid (By similarity). Involved in neurite branching (PubMed:20637285). During optic nerve development, required for SHH-mediated migration and proliferation of oligodendrocyte precursor cells (PubMed:22354480). Mediates endocytic uptake and clearance of SHH in the retinal margin which protects retinal progenitor cells from mitogenic stimuli and keeps them quiescent (PubMed:26439398). Plays a role in reproductive organ development by mediating uptake in reproductive tissues of androgen and estrogen bound to the sex hormone binding protein SHBG (PubMed:16143106). Mediates endocytosis of angiotensin-2 (By similarity). Also mediates endocytosis of angiotensin 1-7 (By similarity). Binds to the complex composed of beta-amyloid protein 40 and CLU/APOJ and mediates its endocytosis and lysosomal degradation (By similarity). Required for embryonic heart development (PubMed:26822476). Required for normal hearing, possibly through interaction with estrogen in the inner ear (PubMed:17846082).[UniProtKB:C0HL13][UniProtKB:P98158][UniProtKB:P98164]^{[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19]}

References

1. ↑ Nykjaer A, Dragun D, Walther D, Vorum H, Jacobsen C, Herz J, Melsen F, Christensen EI, Willnow TE. An endocytic pathway essential for renal uptake and activation of the steroid 25-(OH) vitamin D3. Cell. 1999 Feb 19;96(4):507-15. PMID:10052453 doi:10.1016/s0092-8674(00)80655-8
2. ↑ Hammad SM, Barth JL, Knaak C, Argraves WS. Megalin acts in concert with cubilin to mediate endocytosis of high density lipoproteins. J Biol Chem. 2000 Apr 21;275(16):12003-8. PMID:10766831 doi:10.1074/jbc.275.16.12003
3. ↑ Spoelgen R, Hammes A, Anzenberger U, Zechner D, Andersen OM, Jerchow B, Willnow TE. LRP2/megalin is required for patterning of the ventral telencephalon. Development. 2005 Jan;132(2):405-14. PMID:15623804 doi:10.1242/dev.01580
4. ↑ Hammes A, Andreassen TK, Spoelgen R, Raila J, Hubner N, Schulz H, Metzger J, Schweigert FJ, Luppa PB, Nykjaer A, Willnow TE. Role of endocytosis in cellular uptake of sex steroids. Cell. 2005 Sep 9;122(5):751-62. PMID:16143106 doi:10.1016/j.cell.2005.06.032
5. ↑ Gonzalez-Villalobos R, Klassen RB, Allen PL, Johanson K, Baker CB, Kobori H, Navar LG, Hammond TG. Megalin binds and internalizes angiotensin-(1-7). Am J Physiol Renal Physiol. 2006 May;290(5):F1270-5. PMID:16380466 doi:10.1152/ajprenal.00164.2005
6. ↑ Kaseda R, Iino N, Hosojima M, Takeda T, Hosaka K, Kobayashi A, Yamamoto K, Suzuki A, Kasai A, Suzuki Y, Gejyo F, Saito A. Megalin-mediated endocytosis of cystatin C in proximal tubule cells. Biochem Biophys Res Commun. 2007 Jun 15;357(4):1130-4. PMID:17462596 doi:10.1016/j.bbrc.2007.04.072
7. ↑ König O, Rüttiger L, Müller M, Zimmermann U, Erdmann B, Kalbacher H, Gross M, Knipper M. Estrogen and the inner ear: megalin knockout mice suffer progressive hearing loss. FASEB J. 2008 Feb;22(2):410-7. PMID:17846082 doi:10.1096/fj.07-9171com
8. ↑ Olson GE, Winfrey VP, Hill KE, Burk RF. Megalin mediates selenoprotein P uptake by kidney proximal tubule epithelial cells. J Biol Chem. 2008 Mar 14;283(11):6854-60. PMID:18174160 doi:10.1074/jbc.M709945200
9. ↑ Gajera CR, Emich H, Lioubinski O, Christ A, Beckervordersandforth-Bonk R, Yoshikawa K, Bachmann S, Christensen EI, Götz M, Kempermann G, Peterson AS, Willnow TE, Hammes A. LRP2 in ependymal cells regulates BMP signaling in the adult neurogenic niche. J Cell Sci. 2010 Jun 1;123(Pt 11):1922-30. PMID:20460439 doi:10.1242/jcs.065912
10. ↑ Alvira-Botero X, Pérez-Gonzalez R, Spuch C, Vargas T, Antequera D, Garzón M, Bermejo-Pareja F, Carro E. Megalin interacts with APP and the intracellular adapter protein FE65 in neurons. Mol Cell Neurosci. 2010 Nov;45(3):306-15. PMID:20637285 doi:10.1016/j.mcn.2010.07.005
11. ↑ Christ A, Christa A, Kur E, Lioubinski O, Bachmann S, Willnow TE, Hammes A. LRP2 is an auxiliary SHH receptor required to condition the forebrain ventral midline for inductive signals. Dev Cell. 2012 Feb 14;22(2):268-78. PMID:22340494 doi:10.1016/j.devcel.2011.11.023
12. ↑ Ortega MC, Cases O, Merchán P, Kozyraki R, Clemente D, de Castro F. Megalin mediates the influence of sonic hedgehog on oligodendrocyte precursor cell migration and proliferation during development. Glia. 2012 May;60(6):851-66. PMID:22354480 doi:10.1002/glia.22316
13. ↑ Tam J, Cinar R, Liu J, Godlewski G, Wesley D, Jourdan T, Szanda G, Mukhopadhyay B, Chedester L, Liow JS, Innis RB, Cheng K, Rice KC, Deschamps JR, Chorvat RJ, McElroy JF, Kunos G. Peripheral cannabinoid-1 receptor inverse agonism reduces obesity by reversing leptin resistance. Cell Metab. 2012 Aug 8;16(2):167-79. PMID:22841573 doi:10.1016/j.cmet.2012.07.002
14. ↑ Jobst-Schwan T, Knaup KX, Nielsen R, Hackenbeck T, Buettner-Herold M, Lechler P, Kroening S, Goppelt-Struebe M, Schloetzer-Schrehardt U, Fürnrohr BG, Voll RE, Amann K, Eckardt KU, Christensen EI, Wiesener MS. Renal uptake of the antiapoptotic protein survivin is mediated by megalin at the apical membrane of the proximal tubule. Am J Physiol Renal Physiol. 2013 Sep 1;305(5):F734-44. PMID:23825075 doi:10.1152/ajprenal.00546.2012
15. ↑ Kur E, Mecklenburg N, Cabrera RM, Willnow TE, Hammes A. LRP2 mediates folate uptake in the developing neural tube. J Cell Sci. 2014 May 15;127(Pt 10):2261-8. PMID:24639464 doi:10.1242/jcs.140145
16. ↑ Byun K, Gil SY, Namkoong C, Youn BS, Huang H, Shin MS, Kang GM, Kim HK, Lee B, Kim YB, Kim MS. Clusterin/ApoJ enhances central leptin signaling through Lrp2-mediated endocytosis. EMBO Rep. 2014 Jul;15(7):801-8. PMID:24825475 doi:10.15252/embr.201338317
17. ↑ Christ A, Christa A, Klippert J, Eule JC, Bachmann S, Wallace VA, Hammes A, Willnow TE. LRP2 Acts as SHH Clearance Receptor to Protect the Retinal Margin from Mitogenic Stimuli. Dev Cell. 2015 Oct 12;35(1):36-48. PMID:26439398 doi:10.1016/j.devcel.2015.09.001
18. ↑ Baardman ME, Zwier MV, Wisse LJ, Gittenberger-de Groot AC, Kerstjens-Frederikse WS, Hofstra RM, Jurdzinski A, Hierck BP, Jongbloed MR, Berger RM, Plösch T, DeRuiter MC. Common arterial trunk and ventricular non-compaction in Lrp2 knockout mice indicate a crucial role of LRP2 in cardiac development. Dis Model Mech. 2016 Apr;9(4):413-25. PMID:26822476 doi:10.1242/dmm.022053
19. ↑ Johanns M, Lemoine P, Janssens V, Grieco G, Moestrup SK, Nielsen R, Christensen EI, Courtoy PJ, Emonard H, Marbaix E, Henriet P. Cellular uptake of proMMP-2:TIMP-2 complexes by the endocytic receptor megalin/LRP-2. Sci Rep. 2017 Jun 28;7(1):4328. PMID:28659595 doi:10.1038/s41598-017-04648-y