{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,28]],"date-time":"2025-11-28T17:09:03Z","timestamp":1764349743088},"reference-count":51,"publisher":"American Society of Hematology","issue":"1","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2005,1,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>\u03b22-Integrin clustering on activation is a key event in leukocyte adhesion to the endothelium during the inflammatory response. In the search for molecular mechanisms leading to this clustering, we have identified low-density lipoprotein (LDL) receptor\u2013related protein (LRP) as a new partner for \u03b22-integrins at the leukocyte surface. Immobilized recombinant LRP fragments served as an adhesive surface for blood-derived leukocytes and the U937 cell line. This adhesion was decreased up to 95% in the presence of antibodies against \u03b22-integrins, pointing to these integrins as potential partners for LRP. Using purified proteins, LRP indeed associated with the \u03b1M\u03b22 complex and the \u03b1M and \u03b1L I-domains (Kd, app \u2248 0.5 \u03bcM). Immunoprecipitation experiments and confocal microscopy revealed that endogenously expressed LRP and \u03b1L\u03b22 colocalized in monocytes and U937 cells. Furthermore, activation of U937 cells resulted in clustering of \u03b1L\u03b22 and LRP to similar regions at the cell surface, indicating potential cooperation between both proteins. This was confirmed by the lack of \u03b1L\u03b22 clustering in U937 cells treated by antisense oligonucleotides to down-regulate LRP. In addition, the absence of LRP resulted in complete abrogation of \u03b22-integrin\u2013dependent adhesion to endothelial cells in a perfusion system, demonstrating the presence of a previously unrecognized link between LRP and leukocyte function.<\/jats:p>","DOI":"10.1182\/blood-2004-02-0498","type":"journal-article","created":{"date-parts":[[2004,8,25]],"date-time":"2004-08-25T00:13:16Z","timestamp":1093392796000},"page":"170-177","update-policy":"http:\/\/dx.doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":46,"title":["LDL-receptor\u2013related protein regulates \u03b22-integrin\u2013mediated leukocyte adhesion"],"prefix":"10.1182","volume":"105","author":[{"given":"Patricia P. E. M.","family":"Spijkers","sequence":"first","affiliation":[{"name":"From the Laboratory for Thrombosis and Haemostasis, Department of Haematology, University Medical Center Utrecht, The Netherlands; Department of Experimental Immunohematology, Sanquin Research, Amsterdam, The Netherlands; and Department of Biological and Environmental Sciences, Division of Biochemistry, University of Helsinki, Finland."}]},{"given":"Paula","family":"da Costa Martins","sequence":"additional","affiliation":[{"name":"From the Laboratory for Thrombosis and Haemostasis, Department of Haematology, University Medical Center Utrecht, The Netherlands; Department of Experimental Immunohematology, Sanquin Research, Amsterdam, The Netherlands; and Department of Biological and Environmental Sciences, Division of Biochemistry, University of Helsinki, Finland."}]},{"given":"Erik","family":"Westein","sequence":"additional","affiliation":[{"name":"From the Laboratory for Thrombosis and Haemostasis, Department of Haematology, University Medical Center Utrecht, The Netherlands; Department of Experimental Immunohematology, Sanquin Research, Amsterdam, The Netherlands; and Department of Biological and Environmental Sciences, Division of Biochemistry, University of Helsinki, Finland."}]},{"given":"Carl G.","family":"Gahmberg","sequence":"additional","affiliation":[{"name":"From the Laboratory for Thrombosis and Haemostasis, Department of Haematology, University Medical Center Utrecht, The Netherlands; Department of Experimental Immunohematology, Sanquin Research, Amsterdam, The Netherlands; and Department of Biological and Environmental Sciences, Division of Biochemistry, University of Helsinki, Finland."}]},{"given":"Jaap J.","family":"Zwaginga","sequence":"additional","affiliation":[{"name":"From the Laboratory for Thrombosis and Haemostasis, Department of Haematology, University Medical Center Utrecht, The Netherlands; Department of Experimental Immunohematology, Sanquin Research, Amsterdam, The Netherlands; and Department of Biological and Environmental Sciences, Division of Biochemistry, University of Helsinki, Finland."}]},{"given":"Peter J.","family":"Lenting","sequence":"additional","affiliation":[{"name":"From the Laboratory for Thrombosis and Haemostasis, Department of Haematology, University Medical Center Utrecht, The Netherlands; Department of Experimental Immunohematology, Sanquin Research, Amsterdam, The Netherlands; and Department of Biological and Environmental Sciences, Division of Biochemistry, University of Helsinki, Finland."}]}],"member":"234","reference":[{"key":"2020021220520360300_REF1","doi-asserted-by":"crossref","unstructured":"Herz J, Hamann U, Rogne S, et al. 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;7: 4119-4127.","DOI":"10.1002\/j.1460-2075.1988.tb03306.x"},{"key":"2020021220520360300_REF2","doi-asserted-by":"crossref","unstructured":"Herz J, Kowal RC, Goldstein JL, Brown MS. Proteolytic processing of the 600 kd low density lipoprotein receptor-related protein (LRP) occurs in a trans-Golgi compartment. EMBO J. 1990;9: 1769-1776.","DOI":"10.1002\/j.1460-2075.1990.tb08301.x"},{"key":"2020021220520360300_REF3","doi-asserted-by":"crossref","unstructured":"Willnow TE, Orth K, Herz J. Molecular dissection of ligand binding sites on the low density lipoprotein receptor-related protein. J Biol Chem. 1994; 269: 15827-15832.","DOI":"10.1016\/S0021-9258(17)40755-1"},{"key":"2020021220520360300_REF4","doi-asserted-by":"crossref","unstructured":"Neels JG, van den Berg BM, Lookene A, et al. The second and fourth cluster of class A cysteinerich repeats of the low density lipoprotein receptor-related protein share ligand-binding properties. J Biol Chem. 1999;274: 31305-31311.","DOI":"10.1074\/jbc.274.44.31305"},{"key":"2020021220520360300_REF5","doi-asserted-by":"crossref","unstructured":"Herz J, Strickland DK. LRP: a multifunctional scavenger and signaling receptor. J Clin Invest. 2001;108: 779-784.","DOI":"10.1172\/JCI200113992"},{"key":"2020021220520360300_REF6","doi-asserted-by":"crossref","unstructured":"Li Y, Marzolo MP, van Kerkhof P, Strous GJ, Bu G. The YXXL motif, but not the two NPXY motifs, serves as the dominant endocytosis signal for low density lipoprotein receptor-related protein. J Biol Chem. 2000;275: 17187-17194.","DOI":"10.1074\/jbc.M000490200"},{"key":"2020021220520360300_REF7","doi-asserted-by":"crossref","unstructured":"Gliemann J, Nykjaer A, Petersen CM, et al. The multiligand alpha 2-macroglobulin receptor\/low density lipoprotein receptor-related protein (alpha 2MR\/LRP): binding and endocytosis of fluid phase and membrane-associated ligands. Ann N Y Acad Sci. 1994;737: 20-38.","DOI":"10.1111\/j.1749-6632.1994.tb44299.x"},{"key":"2020021220520360300_REF8","doi-asserted-by":"crossref","unstructured":"Demeule M, Poirier J, Jodoin J, et al. High transcytosis of melanotransferrin (P97) across the blood-brain barrier. J Neurochem. 2002;83: 924-933.","DOI":"10.1046\/j.1471-4159.2002.01201.x"},{"key":"2020021220520360300_REF9","doi-asserted-by":"crossref","unstructured":"Shibata Y, Muramatsu T, Hirai M, et al. Nuclear targeting by the growth factor midkine. Mol Cell Biol. 2002;22: 6788-6796.","DOI":"10.1128\/MCB.22.19.6788-6796.2002"},{"key":"2020021220520360300_REF10","doi-asserted-by":"crossref","unstructured":"Willnow TE, Nykjaer A, Herz J. Lipoprotein receptors: new roles for ancient proteins. Nat Cell Biol. 1999;1: E157-E162.","DOI":"10.1038\/14109"},{"key":"2020021220520360300_REF11","doi-asserted-by":"crossref","unstructured":"Gotthardt M, Trommsdorff M, Nevitt MF, et al. Interactions of the low density lipoprotein receptor gene family with cytosolic adaptor and scaffold proteins suggest diverse biological functions in cellular communication and signal transduction. J Biol Chem. 2000;275: 25616-25624.","DOI":"10.1074\/jbc.M000955200"},{"key":"2020021220520360300_REF12","doi-asserted-by":"crossref","unstructured":"Bacskai BJ, Xia MQ, Strickland DK, Rebeck GW, Hyman BT. The endocytic receptor protein LRP also mediates neuronal calcium signaling via N-methyl-d-aspartate receptors. Proc Natl Acad Sci U S A. 2000;97: 11551-11556.","DOI":"10.1073\/pnas.200238297"},{"key":"2020021220520360300_REF13","doi-asserted-by":"crossref","unstructured":"Boucher P, Liu P, Gotthardt M, et al. Platelet-derived growth factor mediates tyrosine phosphorylation of the cytoplasmic domain of the low density lipoprotein receptor-related protein in caveolae. J Biol Chem. 2002;277: 15507-15513.","DOI":"10.1074\/jbc.M200428200"},{"key":"2020021220520360300_REF14","doi-asserted-by":"crossref","unstructured":"Loukinova E, Ranganathan S, Kuznetsov S, et al. Platelet-derived growth factor (PDGF)-induced tyrosine phosphorylation of the low density lipoprotein receptor-related protein (LRP): evidence for integrated co-receptor function betwenn LRP and the PDGF. J Biol Chem. 2002; 277: 15499-15506.","DOI":"10.1074\/jbc.M200427200"},{"key":"2020021220520360300_REF15","doi-asserted-by":"crossref","unstructured":"Moestrup SK, Gliemann J, Pallesen G. Distribution of the alpha 2-macroglobulin receptor\/low density lipoprotein receptor-related protein in human tissues. Cell Tissue Res. 1992;269: 375-382.","DOI":"10.1007\/BF00353892"},{"key":"2020021220520360300_REF16","doi-asserted-by":"crossref","unstructured":"Moestrup SK, Kaltoft K, Petersen CM, et al. Immunocytochemical identification of the human alpha 2-macroglobulin receptor in monocytes and fibroblasts: monoclonal antibodies define the receptor as a monocyte differentiation antigen. Exp Cell Res. 1990;190: 195-203.","DOI":"10.1016\/0014-4827(90)90185-D"},{"key":"2020021220520360300_REF17","doi-asserted-by":"crossref","unstructured":"Gahmberg CG, Tolvanen M, Kotovuori P. Leukocyte adhesion\u2014structure and function of human leukocyte beta2-integrins and their cellular ligands. Eur J Biochem. 1997;245: 215-232.","DOI":"10.1111\/j.1432-1033.1997.00215.x"},{"key":"2020021220520360300_REF18","doi-asserted-by":"crossref","unstructured":"Diamond MS, Garcia-Aguilar J, Bickford JK, Corbi AL, Springer TA. The I domain is a major recognition site on the leukocyte integrin Mac-1 (CD11b\/CD18) for four distinct adhesion ligands. J Cell Biol. 1993;120: 1031-1043.","DOI":"10.1083\/jcb.120.4.1031"},{"key":"2020021220520360300_REF19","doi-asserted-by":"crossref","unstructured":"Shimaoka M, Takagi J, Springer TA. Conformational regulation of integrin structure and function. Annu Rev Biophys Biomol Struct. 2002;31: 485-516.","DOI":"10.1146\/annurev.biophys.31.101101.140922"},{"key":"2020021220520360300_REF20","doi-asserted-by":"crossref","unstructured":"Dickeson SK, Santoro SA. Ligand recognition by the I domain-containing integrins. Cell Mol Life Sci. 1998;54: 556-566.","DOI":"10.1007\/s000180050184"},{"key":"2020021220520360300_REF21","doi-asserted-by":"crossref","unstructured":"Gahmberg CG. Leukocyte adhesion: CD11\/CD18 integrins and intercellular adhesion molecules. Curr Opin Cell Biol. 1997;9: 643-650.","DOI":"10.1016\/S0955-0674(97)80117-2"},{"key":"2020021220520360300_REF22","doi-asserted-by":"crossref","unstructured":"Hermand P, Huet M, Callebaut I, et al. Binding sites of leukocyte beta 2 integrins (LFA-1, Mac-1) on the human ICAM-4\/LW blood group protein. J Biol Chem. 2000;275: 26002-26010.","DOI":"10.1074\/jbc.M002823200"},{"key":"2020021220520360300_REF23","doi-asserted-by":"crossref","unstructured":"Tian L, Yoshihara Y, Mizuno T, Mori K, Gahmberg CG. The neuronal glycoprotein telencephalin is a cellular ligand for the CD11a\/CD18 leukocyte integrin. J Immunol. 1997;158: 928-936.","DOI":"10.4049\/jimmunol.158.2.928"},{"key":"2020021220520360300_REF24","doi-asserted-by":"crossref","unstructured":"Ostermann G, Weber KS, Zernecke A, Schroder A, Weber C. JAM-1 is a ligand of the beta(2) integrin LFA-1 involved in transendothelial migration of leukocytes. Nat Immunol. 2002;3: 151-158.","DOI":"10.1038\/ni755"},{"key":"2020021220520360300_REF25","doi-asserted-by":"crossref","unstructured":"Santoso S, Sachs UJ, Kroll H, et al. The junctional adhesion molecule 3 (JAM-3) on human platelets is a counterreceptor for the leukocyte integrin Mac-1. J Exp Med. 2002;196: 679-691.","DOI":"10.1084\/jem.20020267"},{"key":"2020021220520360300_REF26","doi-asserted-by":"crossref","unstructured":"Ehlers R, Ustinov V, Chen Z, et al. Targeting platelet-leukocyte interactions: identification of the integrin Mac-1 binding site for the platelet counter receptor glycoprotein Ibalpha. J Exp Med. 2003;198: 1077-1088.","DOI":"10.1084\/jem.20022181"},{"key":"2020021220520360300_REF27","doi-asserted-by":"crossref","unstructured":"Simon DI, Chen Z, Xu H, et al. Platelet glycoprotein Ib-alpha is a counterreceptor for the leukocyte integrin Mac-1 (CD11b\/CD18). J Exp Med. 2000;192: 193-204.","DOI":"10.1084\/jem.192.2.193"},{"key":"2020021220520360300_REF28","doi-asserted-by":"crossref","unstructured":"Hoffmeister KM, Josefsson EC, Isaac NA, et al. Glycosylation restores survival of chilled blood platelets. Science. 2003;301: 1531-1534.","DOI":"10.1126\/science.1085322"},{"key":"2020021220520360300_REF29","doi-asserted-by":"crossref","unstructured":"Harris ES, McIntyre TM, Prescott SM, Zimmerman GA. The leukocyte integrins. J Biol Chem. 2000;275: 23409-23412.","DOI":"10.1074\/jbc.R000004200"},{"key":"2020021220520360300_REF30","doi-asserted-by":"crossref","unstructured":"Springer TA. Traffic signals on endothelium for lymphocyte recirculation and leukocyte emigration. Annu Rev Physiol. 1995;57: 827-872.","DOI":"10.1146\/annurev.ph.57.030195.004143"},{"key":"2020021220520360300_REF31","doi-asserted-by":"crossref","unstructured":"Nortamo P, Patarroyo M, Kantor C, Suopanki J, Gahmberg CG. Immunological mapping of the human leucocyte adhesion glycoprotein gp90 (CD18) by monoclonal antibodies. Scand J Immunol. 1988;28: 537-546.","DOI":"10.1111\/j.1365-3083.1988.tb01485.x"},{"key":"2020021220520360300_REF32","doi-asserted-by":"crossref","unstructured":"Herz J, Goldstein JL, Strickland DK, Ho YK, Brown MS. 39-kDa protein modulates binding of ligands to low density lipoprotein receptor-related protein\/alpha 2-macroglobulin receptor. J Biol Chem. 1991;266: 21232-21238.","DOI":"10.1016\/S0021-9258(18)54845-6"},{"key":"2020021220520360300_REF33","doi-asserted-by":"crossref","unstructured":"Lenting PJ, Neels JG, van den Berg BM, et al. The light chain of factor VIII comprises a binding site for low density lipoprotein receptor-related protein. J Biol Chem. 1999;274: 23734-23739.","DOI":"10.1074\/jbc.274.34.23734"},{"key":"2020021220520360300_REF34","doi-asserted-by":"crossref","unstructured":"Ihanus E, Uotila L, Toivanen A, et al. Characterization of ICAM-4 binding to the I domains of the CD11a\/CD18 and CD11b\/CD18 leukocyte integrins. Eur J Biochem. 2003;270: 1710-1723.","DOI":"10.1046\/j.1432-1033.2003.03528.x"},{"key":"2020021220520360300_REF35","doi-asserted-by":"crossref","unstructured":"Yatohgo T, Izumi M, Kashiwagi H, Hayashi M. Novel purification of vitronectin from human plasma by heparin affinity chromatography. Cell Struct Funct. 1988;13: 281-292.","DOI":"10.1247\/csf.13.281"},{"key":"2020021220520360300_REF36","doi-asserted-by":"crossref","unstructured":"Jaffe EA, Nachman RL, Becker CG, Minick CR. Culture of human endothelial cells derived from umbilical veins: identification by morphologic and immunologic criteria. J Clin Invest. 1973;52: 2745-2756.","DOI":"10.1172\/JCI107470"},{"key":"2020021220520360300_REF37","doi-asserted-by":"crossref","unstructured":"Willems C, Astaldi GC, de Groot PG, et al. Media conditioned by cultured human vascular endothelial cells inhibit the growth of vascular smooth muscle cells. Exp Cell Res. 1982;139: 191-197.","DOI":"10.1016\/0014-4827(82)90332-9"},{"key":"2020021220520360300_REF38","doi-asserted-by":"crossref","unstructured":"Sundstrom C, Nilsson K. Establishment and characterization of a human histiocytic lymphoma cell line (U-937). Int J Cancer. 1976;17: 565-577.","DOI":"10.1002\/ijc.2910170504"},{"key":"2020021220520360300_REF39","doi-asserted-by":"crossref","unstructured":"Llorente-Cortes V, Martinez-Gonzalez J, Badimon L. LDL receptor-related protein mediates uptake of aggregated LDL in human vascular smooth muscle cells. Arterioscler Thromb Vasc Biol. 2000;20: 1572-1579.","DOI":"10.1161\/01.ATV.20.6.1572"},{"key":"2020021220520360300_REF40","doi-asserted-by":"crossref","unstructured":"Lenting PJ, Westein E, Terraube V, et al. An experimental model to study the in vivo survival of von Willebrand factor: basic aspects and application to the R1205H mutation. J Biol Chem. 2004; 279: 12102-12109.","DOI":"10.1074\/jbc.M310436200"},{"key":"2020021220520360300_REF41","doi-asserted-by":"crossref","unstructured":"Heijnen HF, Van Lier M, Waaijenborg S, et al. Concentration of rafts in platelet filopodia correlates with recruitment of c-Src and CD63 to these domains. J Thromb Haemost. 2003;1: 1161-1173.","DOI":"10.1046\/j.1538-7836.2003.00316.x"},{"key":"2020021220520360300_REF42","unstructured":"Sakariassen KS, Aarts PA, de Groot PG, Houdijk WP, Sixma JJ. A perfusion chamber developed to investigate platelet interaction in flowing blood with human vessel wall cells, their extracellular matrix, and purified components. J Lab Clin Med. 1983;102: 522-535."},{"key":"2020021220520360300_REF43","doi-asserted-by":"crossref","unstructured":"van Zanten H, Saelman EU, Schut-Hese KM, et al. Platelet adhesion to collagen type IV under flow conditions. Blood. 1996;88: 3862-3871.","DOI":"10.1182\/blood.V88.10.3862.bloodjournal88103862"},{"key":"2020021220520360300_REF44","doi-asserted-by":"crossref","unstructured":"Krauss K, Altevogt P. Integrin leukocyte function-associated antigen-1-mediated cell binding can be activated by clustering of membrane rafts. J Biol Chem. 1999;274: 36921-36927.","DOI":"10.1074\/jbc.274.52.36921"},{"key":"2020021220520360300_REF45","doi-asserted-by":"crossref","unstructured":"Krieger M, Stern DM. Series introduction: multiligand receptors and human disease. J Clin Invest. 2001;108: 645-647.","DOI":"10.1172\/JCI200113932"},{"key":"2020021220520360300_REF46","doi-asserted-by":"crossref","unstructured":"Yepes M, Sandkvist M, Moore EG, et al. Tissue-type plasminogen activator induces opening of the blood-brain barrier via the LDL receptor-related protein. J Clin Invest. 2003;112: 1533-1540.","DOI":"10.1172\/JCI200319212"},{"key":"2020021220520360300_REF47","doi-asserted-by":"crossref","unstructured":"Salicioni AM, Gaultier A, Brownlee C, Cheezum MK, Gonias SL. Low density lipoprotein receptor-related protein-1 promotes beta1 integrin maturation and transport to the cell surface. J Biol Chem. 2004;279: 10005-10012.","DOI":"10.1074\/jbc.M306625200"},{"key":"2020021220520360300_REF48","doi-asserted-by":"crossref","unstructured":"Czekay RP, Aertgeerts K, Curriden SA, Loskutoff DJ. Plasminogen activator inhibitor-1 detaches cells from extracellular matrices by inactivating integrins. J Cell Biol. 2003;160: 781-791.","DOI":"10.1083\/jcb.200208117"},{"key":"2020021220520360300_REF49","doi-asserted-by":"crossref","unstructured":"Krauss K, Altevogt P. Integrin leukocyte function-associated antigen-1-mediated cell binding can be activated by clustering of membrane rafts. J Biol Chem. 1999;274: 36921-36927.","DOI":"10.1074\/jbc.274.52.36921"},{"key":"2020021220520360300_REF50","doi-asserted-by":"crossref","unstructured":"Stefanidakis M, Bjorklund M, Ihanus E, Gahmberg CG, Koivunen E. Identification of a negatively charged peptide motif within the catalytic domain of progelatinases that mediates binding to leukocyte beta 2 integrins. J Biol Chem. 2003; 278: 34674-34684.","DOI":"10.1074\/jbc.M302288200"},{"key":"2020021220520360300_REF51","doi-asserted-by":"crossref","unstructured":"Czekay RP, Kuemmel TA, Orlando RA, Farquhar MG. Direct binding of occupied urokinase receptor (uPAR) to LDL receptor-related protein is required for endocytosis of uPAR and regulation of cell surface urokinase activity. Mol Biol Cell. 2001;12: 1467-1479.","DOI":"10.1091\/mbc.12.5.1467"}],"container-title":["Blood"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/ashpublications.org\/blood\/article-pdf\/105\/1\/170\/1705006\/zh800105000170.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/ashpublications.org\/blood\/article-pdf\/105\/1\/170\/1705006\/zh800105000170.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,4,29]],"date-time":"2023-04-29T06:48:56Z","timestamp":1682750936000},"score":1,"resource":{"primary":{"URL":"https:\/\/ashpublications.org\/blood\/article\/105\/1\/170\/20016\/LDLreceptorrelated-protein-regulates"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2005,1,1]]},"references-count":51,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2005,1,1]]}},"URL":"https:\/\/doi.org\/10.1182\/blood-2004-02-0498","relation":{},"ISSN":["0006-4971","1528-0020"],"issn-type":[{"value":"0006-4971","type":"print"},{"value":"1528-0020","type":"electronic"}],"subject":[],"published":{"date-parts":[[2005,1,1]]}}}