Key points are not available for this paper at this time.
The low density lipoprotein receptor-related protein-deleted in tumor (LRP1B, initially referred to as LRP-DIT) was cloned and characterized as a candidate tumor suppressor. It is a new member of the low density lipoprotein receptor gene family. Its overall domain structure and large size (∼600 kDa) are similar to LRP and suggest that it is a multifunctional cell surface receptor. Herein, we characterize a series of ligands for the receptor using cell lines that stably express it as a domain IV minireceptor (mLRP1B4). Ligands of LRP including receptor-associated protein, urokinase plasminogen activator, tissue-type plasminogen activator, and plasminogen activator inhibitor type-1 each demonstrate binding, internalization, and degradation via mLRP1B4. Interestingly, the kinetics of ligand endocytosis is distinctly different from that of LRP, with LRP1B exhibiting a markedly diminished internalization rate. In addition, tissue expression analysis reveals that the LRP1B gene is expressed in brain, thyroid, and salivary gland. These studies thus extend the physiological roles of members of the LDL receptor family. The low density lipoprotein receptor-related protein-deleted in tumor (LRP1B, initially referred to as LRP-DIT) was cloned and characterized as a candidate tumor suppressor. It is a new member of the low density lipoprotein receptor gene family. Its overall domain structure and large size (∼600 kDa) are similar to LRP and suggest that it is a multifunctional cell surface receptor. Herein, we characterize a series of ligands for the receptor using cell lines that stably express it as a domain IV minireceptor (mLRP1B4). Ligands of LRP including receptor-associated protein, urokinase plasminogen activator, tissue-type plasminogen activator, and plasminogen activator inhibitor type-1 each demonstrate binding, internalization, and degradation via mLRP1B4. Interestingly, the kinetics of ligand endocytosis is distinctly different from that of LRP, with LRP1B exhibiting a markedly diminished internalization rate. In addition, tissue expression analysis reveals that the LRP1B gene is expressed in brain, thyroid, and salivary gland. These studies thus extend the physiological roles of members of the LDL receptor family. low density lipoprotein receptor-related protein receptor-associated protein urokinase plasminogen activator plasminogen activator inhibitor type-1 tissue-type plasminogen activator single chain uPA hemagglutinin polymerase chain reaction Chinese hamster ovary uPA receptor Members of the low density lipoprotein receptor gene family play a wide variety of roles in normal cell function and development. For example, mutations of the low density lipoprotein receptor gene, the prototypic family member, result in the genetic disease familial hypercholesterolemia (1Brown M.S. Goldstein J.L. Science. 1986; 232: 34-37Crossref PubMed Scopus (4307) Google Scholar). Much attention has focused on other members of this gene family (including LRP,1 megalin, apolipoprotein E receptor-2, very low density lipoprotein receptor) because of their recently recognized roles in development, cell signaling, and pathogenesis (2Howell B.W. Herz J. Curr. Opin. Neurobiol. 2001; 11: 74-81Crossref PubMed Scopus (68) Google Scholar, 3Ulery P.G. Strickland D.K. J. Clin. Invest. 2000; 106: 1077-1079Crossref PubMed Scopus (38) Google Scholar). The low density lipoprotein receptor-related protein LRP1B (initially referred to as LRP-DIT (deleted in tumor)), a candidate tumor suppressor, is a new member of the giant receptor subgroup of this gene family. It is located at chromosome 2q21.2 and was isolated by positional cloning based on homozygous deletions detected in human cancer cell lines (4Liu C.-X. Musco S. Lisitsina N.M. Fogacs E. Minna J.D. Lisitsyn N.A. Cancer Res. 2000; 60: 1961-1967PubMed Google Scholar, 5Liu C.-X. Musco S. Lisitsina N.M. Yaklichkin S.Y. Lisitsyn N.A. Genomics. 2000; 69: 271-274Crossref PubMed Scopus (59) Google Scholar, 6Lisitsyn N.A. Lisitsina N.M. Dalbagni G. Barker P. Sanchez C.A. Gnarra J. Linehan W.M. Reid B.J. Wigler M.H. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 151-155Crossref PubMed Scopus (116) Google Scholar). Mutation analysis revealed that the gene is frequently (45%) inactivated in human non-small cell lung cancer cell lines by intragenic homozygous deletions, point mutations, and aberrant transcripts missing internal portions. Loss of heterozygosity analysis also detected high allelic loss within the locus using two independent microsatellite polymorphism markers, suggesting that the gene is a candidate tumor suppressor (4Liu C.-X. Musco S. Lisitsina N.M. Fogacs E. Minna J.D. Lisitsyn N.A. Cancer Res. 2000; 60: 1961-1967PubMed Google Scholar).The low density lipoprotein receptor gene family previously contained two very large members, LRP (LRP1), a dimer of 515 and 85 kDa, and its closely related homolog, megalin (LRP2), a single species of ∼600 kDa (2Howell B.W. Herz J. Curr. Opin. Neurobiol. 2001; 11: 74-81Crossref PubMed Scopus (68) Google Scholar, 3Ulery P.G. Strickland D.K. J. Clin. Invest. 2000; 106: 1077-1079Crossref PubMed Scopus (38) Google Scholar). LRP1B is more closely related to LRP (with similarity of 59 and 52% identity at the cDNA and predicted amino acid levels, respectively) than to LRP2 (4Liu C.-X. Musco S. Lisitsina N.M. Fogacs E. Minna J.D. Lisitsyn N.A. Cancer Res. 2000; 60: 1961-1967PubMed Google Scholar). The cDNA of LRP1B is 16.5 kilobases, with an open reading frame of 13,797 base pairs, which encodes a protein of 4599 amino acids. Characterization of exon-intron boundaries determined that the genomic DNA of LRP1B contains 91 exons, 89 of which are nearly identical in size and location to those of the 89 exons in the LRP gene (4Liu C.-X. Musco S. Lisitsina N.M. Fogacs E. Minna J.D. Lisitsyn N.A. Cancer Res. 2000; 60: 1961-1967PubMed Google Scholar, 5Liu C.-X. Musco S. Lisitsina N.M. Yaklichkin S.Y. Lisitsyn N.A. Genomics. 2000; 69: 271-274Crossref PubMed Scopus (59) Google Scholar). The two extra exons in LRP1B, exon 68 and exon 90, have no counterparts in LRP. However, the average size of the introns in LRP1B is at least 10 times larger than that of LRP (5Liu C.-X. Musco S. Lisitsina N.M. Yaklichkin S.Y. Lisitsyn N.A. Genomics. 2000; 69: 271-274Crossref PubMed Scopus (59) Google Scholar). Protein domain structure comparison of the two genes reveals that the overall domain structural organizations of the two proteins are almost identical to one another, except for the fragments encoded by the two extra exons in LRP1B (4; see Fig. 1). Similar to LRP, LRP1B protein has four putative ligand-binding domains (I, II, III, and IV from the amino terminus) that consist of 2, 8, 10, and 12 cysteine-rich ligand-binding repeats, respectively. As in LRP, these domain clusters are separated from one another by three clusters of epidermal growth factor precursor repeats and (F/Y)WXD spacer repeats. The number and arrangement of the two types of repeats are the same as those found in LRP, except for the one additional ligand-binding repeat in domain IV, which is encoded by exon 68. LRP1B also contains a putative furin endopeptidase processing site (REKR) at positions 3954–3957 (4Liu C.-X. Musco S. Lisitsina N.M. Fogacs E. Minna J.D. Lisitsyn N.A. Cancer Res. 2000; 60: 1961-1967PubMed Google Scholar), similar to that in LRP (7Herz J. Kowal R.C. Goldstein J.L. Brown M.S. EMBO J. 1990; 9: 1769-1776Crossref PubMed Scopus (210) Google Scholar, N.M. Herz J. J. PubMed Scopus Google Scholar). processing in the of LRP as a of an and a (7Herz J. Kowal R.C. Goldstein J.L. Brown M.S. EMBO J. 1990; 9: 1769-1776Crossref PubMed Scopus (210) Google N.M. Herz J. J. PubMed Scopus Google Scholar). The domain of LRP1B is separated from domain IV and by a of epidermal growth precursor repeats. The of LRP1B contains two these two is a of amino acid by exon in LRP (4Liu C.-X. Musco S. Lisitsina N.M. Fogacs E. Minna J.D. Lisitsyn N.A. Cancer Res. 2000; 60: 1961-1967PubMed Google is expressed and roles in lipoprotein cell and and pathogenesis of disease (2Howell B.W. Herz J. Curr. Opin. Neurobiol. 2001; 11: 74-81Crossref PubMed Scopus (68) Google Scholar, 3Ulery P.G. Strickland D.K. J. Clin. Invest. 2000; 106: 1077-1079Crossref PubMed Scopus (38) Google Scholar, Strickland D.K. A. PubMed Scopus Google Scholar). The LRP gene is also for J. PubMed Scopus Google J. PubMed Scopus Google Scholar). in is by the of LRP with including and lipoprotein Strickland D.K. A. PubMed Scopus Google Scholar). LRP is also in J. PubMed Scopus Google Scholar, B.J. Strickland D.K. Proc. Natl. Acad. Sci. U. S. A. 2000; PubMed Scopus Google Scholar, J. G. J. 2000; PubMed Google Scholar). its LRP the urokinase plasminogen activator A. J. J. PubMed Google Scholar, J. Strickland D.K. J. PubMed Google Scholar, A. J. J. 1995; PubMed Scopus Google Scholar, A. J. EMBO J. PubMed Scopus Google Scholar, A. J. J. PubMed Scopus Google Scholar, Strickland D.K. J. PubMed Scopus Google Scholar, J. Sci. 2000; PubMed Google Scholar). The similarity in protein domain structure LRP1B and LRP that the two similarity in ligand ligands for LRP also ligands for is by the that LRP2 ligands for LRP, as receptor-associated protein and urokinase plasminogen activator with plasminogen activator inhibitor type-1 their is as high as that LRP and of the as apolipoprotein E and of the of the gene family Strickland D.K. A. PubMed Scopus Google Scholar). is a protein that to LRP and the of other ligands of LRP G. PubMed Scopus Google Scholar). as a for LRP receptor G. PubMed Scopus Google Scholar). In this we the and of a minireceptor of LRP1B and its to and LRP ligands including and tissue-type plasminogen activator on its predicted amino acid LRP1B is a new member of the low density lipoprotein receptor gene family with a size (∼600 kDa) similar to that of LRP and LRP1B is more closely related to LRP than to at the amino acid and in its domain structural Fig. 1). These structural suggest that the ligands of the as as the function of the studies have of LRP1B and LRP. have that is expressed at the cell surface and is by the furin within the the cell and each of the four LRP ligands and the of each of these ligands to as it to these LRP1B and LRP in two the kinetics of ligand endocytosis determined with are distinctly different these two and similar for ligand and of ligand the internalization and is for mLRP1B4. The of internalization is more than for which in by the at the cell The physiological of this is the of LRP1B as a protein receptor internalization for cell surface LRP1B found to play a in because other members of this receptor family have found to play a in (2Howell B.W. Herz J. Curr. Opin. Neurobiol. 2001; 11: 74-81Crossref PubMed Scopus (68) Google Scholar). the within the of LRP and LRP1B is the acid in the of with proteins and thus a for the internalization of studies similar to those that have the within the of LRP and apolipoprotein E Herz J. J. J. 2000; PubMed Scopus Google Scholar, J. J. Herz J. J. 2000; PubMed Scopus Google this the expression of LRP, LRP1B, and other family members LRP is expressed in brain, and In LRP is a receptor for of and J. PubMed Scopus Google Scholar), in LRP an in growth J. G. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: PubMed Scopus Google Scholar, G. J. PubMed Scopus Google and is in the of disease P.G. Strickland D.K. J. Clin. Invest. 2000; 106: 1077-1079Crossref PubMed Scopus (38) Google and J. G. J. 2000; PubMed Google Scholar). is expressed in with expression in lung and In it as an receptor of and other A. Herz J. PubMed Scopus Google Scholar). LRP1B is expressed in brain, thyroid, and salivary a from those of the other of the gene family. more of LRP1B expression via with an with the it of uPA and as ligands for LRP1B because are of the uPA one of the Sci. 2000; PubMed Scopus Google Scholar, P. Cancer Res. 2000; PubMed Google Scholar). The uPA a in cancer and as as other physiological and in tissue the that a of the uPA in cell and independent from its is the and other cell surface and Sci. 2000; PubMed Scopus Google Scholar, P. Cancer Res. 2000; PubMed Google Scholar). LRP is recognized as one of and function A. J. J. PubMed Google Scholar, J. Strickland D.K. J. PubMed Google Scholar, A. J. J. 1995; PubMed Scopus Google Scholar, A. J. EMBO J. PubMed Scopus Google Scholar, A. J. J. PubMed Scopus Google Scholar, Strickland D.K. J. PubMed Scopus Google Scholar, J. Sci. 2000; PubMed Google Scholar). to cell surface with high and is uPA the of the plasminogen to which in the degradation of including uPA by with the of a The to LRP with high and is with the ligand to for and LRP to the cell surface A. J. J. 1995; PubMed Scopus Google Scholar, A. J. EMBO J. PubMed Scopus Google Scholar). similar of LRP1B and its to LRP1B was via its homozygous deletions in human cancer cell lines and thus a candidate tumor suppressor. analysis that it was frequently inactivated in cell lines of human lung cancer (4Liu C.-X. Musco S. Lisitsina N.M. Fogacs E. Minna J.D. Lisitsyn N.A. Cancer Res. 2000; 60: 1961-1967PubMed Google Scholar). which that LRP1B with uPA and studies on the function of LRP1B in the function of the and in tumor using LRP1B minireceptor we that and are ligands for However, LRP1B from LRP in kinetics and in its tissue expression studies on its physiological and roles as as the Members of the low density lipoprotein receptor gene family play a wide variety of roles in normal cell function and development. For example, mutations of the low density lipoprotein receptor gene, the prototypic family member, result in the genetic disease familial hypercholesterolemia (1Brown M.S. Goldstein J.L. Science. 1986; 232: 34-37Crossref PubMed Scopus (4307) Google Scholar). Much attention has focused on other members of this gene family (including LRP,1 megalin, apolipoprotein E receptor-2, very low density lipoprotein receptor) because of their recently recognized roles in development, cell signaling, and pathogenesis (2Howell B.W. Herz J. Curr. Opin. Neurobiol. 2001; 11: 74-81Crossref PubMed Scopus (68) Google Scholar, 3Ulery P.G. Strickland D.K. J. Clin. Invest. 2000; 106: 1077-1079Crossref PubMed Scopus (38) Google Scholar). The low density lipoprotein receptor-related protein LRP1B (initially referred to as LRP-DIT (deleted in tumor)), a candidate tumor suppressor, is a new member of the giant receptor subgroup of this gene family. It is located at chromosome 2q21.2 and was isolated by positional cloning based on homozygous deletions detected in human cancer cell lines (4Liu C.-X. Musco S. Lisitsina N.M. Fogacs E. Minna J.D. Lisitsyn N.A. Cancer Res. 2000; 60: 1961-1967PubMed Google Scholar, 5Liu C.-X. Musco S. Lisitsina N.M. Yaklichkin S.Y. Lisitsyn N.A. Genomics. 2000; 69: 271-274Crossref PubMed Scopus (59) Google Scholar, 6Lisitsyn N.A. Lisitsina N.M. Dalbagni G. Barker P. Sanchez C.A. Gnarra J. Linehan W.M. Reid B.J. Wigler M.H. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 151-155Crossref PubMed Scopus (116) Google Scholar). Mutation analysis revealed that the gene is frequently (45%) inactivated in human non-small cell lung cancer cell lines by intragenic homozygous deletions, point mutations, and aberrant transcripts missing internal portions. Loss of heterozygosity analysis also detected high allelic loss within the locus using two independent microsatellite polymorphism markers, suggesting that the gene is a candidate tumor suppressor (4Liu C.-X. Musco S. Lisitsina N.M. Fogacs E. Minna J.D. Lisitsyn N.A. Cancer Res. 2000; 60: 1961-1967PubMed Google Scholar). The low density lipoprotein receptor gene family previously contained two very large members, LRP (LRP1), a dimer of 515 and 85 kDa, and its closely related homolog, megalin (LRP2), a single species of ∼600 kDa (2Howell B.W. Herz J. Curr. Opin. Neurobiol. 2001; 11: 74-81Crossref PubMed Scopus (68) Google Scholar, 3Ulery P.G. Strickland D.K. J. Clin. Invest. 2000; 106: 1077-1079Crossref PubMed Scopus (38) Google Scholar). LRP1B is more closely related to LRP (with similarity of 59 and 52% identity at the cDNA and predicted amino acid levels, respectively) than to LRP2 (4Liu C.-X. Musco S. Lisitsina N.M. Fogacs E. Minna J.D. Lisitsyn N.A. Cancer Res. 2000; 60: 1961-1967PubMed Google Scholar). The cDNA of LRP1B is 16.5 kilobases, with an open reading frame of 13,797 base pairs, which encodes a protein of 4599 amino acids. Characterization of exon-intron boundaries determined that the genomic DNA of LRP1B contains 91 exons, 89 of which are nearly identical in size and location to those of the 89 exons in the LRP gene (4Liu C.-X. Musco S. Lisitsina N.M. Fogacs E. Minna J.D. Lisitsyn N.A. Cancer Res. 2000; 60: 1961-1967PubMed Google Scholar, 5Liu C.-X. Musco S. Lisitsina N.M. Yaklichkin S.Y. Lisitsyn N.A. Genomics. 2000; 69: 271-274Crossref PubMed Scopus (59) Google Scholar). The two extra exons in LRP1B, exon 68 and exon 90, have no counterparts in LRP. However, the average size of the introns in LRP1B is at least 10 times larger than that of LRP (5Liu C.-X. Musco S. Lisitsina N.M. Yaklichkin S.Y. Lisitsyn N.A. Genomics. 2000; 69: 271-274Crossref PubMed Scopus (59) Google Scholar). Protein domain structure comparison of the two genes reveals that the overall domain structural organizations of the two proteins are almost identical to one another, except for the fragments encoded by the two extra exons in LRP1B (4; see Fig. 1). Similar to LRP, LRP1B protein has four putative ligand-binding domains (I, II, III, and IV from the amino terminus) that consist of 2, 8, 10, and 12 cysteine-rich ligand-binding repeats, respectively. As in LRP, these domain clusters are separated from one another by three clusters of epidermal growth factor precursor repeats and (F/Y)WXD spacer repeats. The number and arrangement of the two types of repeats are the same as those found in LRP, except for the one additional ligand-binding repeat in domain IV, which is encoded by exon 68. LRP1B also contains a putative furin endopeptidase processing site (REKR) at positions 3954–3957 (4Liu C.-X. Musco S. Lisitsina N.M. Fogacs E. Minna J.D. Lisitsyn N.A. Cancer Res. 2000; 60: 1961-1967PubMed Google Scholar), similar to that in LRP (7Herz J. Kowal R.C. Goldstein J.L. Brown M.S. EMBO J. 1990; 9: 1769-1776Crossref PubMed Scopus (210) Google Scholar, N.M. Herz J. J. PubMed Scopus Google Scholar). processing in the of LRP as a of an and a (7Herz J. Kowal R.C. Goldstein J.L. Brown M.S. EMBO J. 1990; 9: 1769-1776Crossref PubMed Scopus (210) Google N.M. Herz J. J. PubMed Scopus Google Scholar). The domain of LRP1B is separated from domain IV and by a of epidermal growth precursor repeats. The of LRP1B contains two these two is a of amino acid by exon in LRP (4Liu C.-X. Musco S. Lisitsina N.M. Fogacs E. Minna J.D. Lisitsyn N.A. Cancer Res. 2000; 60: 1961-1967PubMed Google Scholar). LRP is expressed and roles in lipoprotein cell and and pathogenesis of disease (2Howell B.W. Herz J. Curr. Opin. Neurobiol. 2001; 11: 74-81Crossref PubMed Scopus (68) Google Scholar, 3Ulery P.G. Strickland D.K. J. Clin. Invest. 2000; 106: 1077-1079Crossref PubMed Scopus (38) Google Scholar, Strickland D.K. A. PubMed Scopus Google Scholar). The LRP gene is also for J. PubMed Scopus Google J. PubMed Scopus Google Scholar). in is by the of LRP with including and lipoprotein Strickland D.K. A. PubMed Scopus Google Scholar). LRP is also in J. PubMed Scopus Google Scholar, B.J. Strickland D.K. Proc. Natl. Acad. Sci. U. S. A. 2000; PubMed Scopus Google Scholar, J. G. J. 2000; PubMed Google Scholar). its LRP the urokinase plasminogen activator A. J. J. PubMed Google Scholar, J. Strickland D.K. J. PubMed Google Scholar, A. J. J. 1995; PubMed Scopus Google Scholar, A. J. EMBO J. PubMed Scopus Google Scholar, A. J. J. PubMed Scopus Google Scholar, Strickland D.K. J. PubMed Scopus Google Scholar, J. Sci. 2000; PubMed Google Scholar). The similarity in protein domain structure LRP1B and LRP that the two similarity in ligand ligands for LRP also ligands for is by the that LRP2 ligands for LRP, as receptor-associated protein and urokinase plasminogen activator with plasminogen activator inhibitor type-1 their is as high as that LRP and of the as apolipoprotein E and of the of the gene family Strickland D.K. A. PubMed Scopus Google Scholar). is a protein that to LRP and the of other ligands of LRP G. PubMed Scopus Google Scholar). as a for LRP receptor G. PubMed Scopus Google Scholar). In this we the and of a minireceptor of LRP1B and its to and LRP ligands including and tissue-type plasminogen activator on its predicted amino acid LRP1B is a new member of the low density lipoprotein receptor gene family with a size (∼600 kDa) similar to that of LRP and LRP1B is more closely related to LRP than to at the amino acid and in its domain structural Fig. 1). These structural suggest that the ligands of the as as the function of the studies have of LRP1B and LRP. have that is expressed at the cell surface and is by the furin within the the cell and each of the four LRP ligands and the of each of these ligands to as it to these LRP1B and LRP in two the kinetics of ligand endocytosis determined with are distinctly different these two and similar for ligand and of ligand the internalization and is for mLRP1B4. The of internalization is more than for which in by the at the cell The physiological of this is the of LRP1B as a protein receptor internalization for cell surface LRP1B found to play a in because other members of this receptor family have found to play a in (2Howell B.W. Herz J. Curr. Opin. Neurobiol. 2001; 11: 74-81Crossref PubMed Scopus (68) Google Scholar). the within the of LRP and LRP1B is the acid in the of with proteins and thus a for the internalization of studies similar to those that have the within the of LRP and apolipoprotein E Herz J. J. J. 2000; PubMed Scopus Google Scholar, J. J. Herz J. J. 2000; PubMed Scopus Google this the expression of LRP, LRP1B, and other family members LRP is expressed in brain, and In LRP is a receptor for of and J. PubMed Scopus Google Scholar), in LRP an in growth J. G. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: PubMed Scopus Google Scholar, G. J. PubMed Scopus Google and is in the of disease P.G. Strickland D.K. J. Clin. Invest. 2000; 106: 1077-1079Crossref PubMed Scopus (38) Google and J. G. J. 2000; PubMed Google Scholar). is expressed in with expression in lung and In it as an receptor of and other A. Herz J. PubMed Scopus Google Scholar). LRP1B is expressed in brain, thyroid, and salivary a from those of the other of the gene family. more of LRP1B expression via with an with the it of uPA and as ligands for LRP1B because are of the uPA one of the Sci. 2000; PubMed Scopus Google Scholar, P. Cancer Res. 2000; PubMed Google Scholar). The uPA a in cancer and as as other physiological and in tissue the that a of the uPA in cell and independent from its is the and other cell surface and Sci. 2000; PubMed Scopus Google Scholar, P. Cancer Res. 2000; PubMed Google Scholar). LRP is recognized as one of and function A. J. J. PubMed Google Scholar, J. Strickland D.K. J. PubMed Google Scholar, A. J. J. 1995; PubMed Scopus Google Scholar, A. J. EMBO J. PubMed Scopus Google Scholar, A. J. J. PubMed Scopus Google Scholar, Strickland D.K. J. PubMed Scopus Google Scholar, J. Sci. 2000; PubMed Google Scholar). to cell surface with high and is uPA the of the plasminogen to which in the degradation of including uPA by with the of a The to LRP with high and is with the ligand to for and LRP to the cell surface A. J. J. 1995; PubMed Scopus Google Scholar, A. J. EMBO J. PubMed Scopus Google Scholar). similar of LRP1B and its to LRP1B was via its homozygous deletions in human cancer cell lines and thus a candidate tumor suppressor. analysis that it was frequently inactivated in cell lines of human lung cancer (4Liu C.-X. Musco S. Lisitsina N.M. Fogacs E. Minna J.D. Lisitsyn N.A. Cancer Res. 2000; 60: 1961-1967PubMed Google Scholar). which that LRP1B with uPA and studies on the function of LRP1B in the function of the and in tumor using LRP1B minireceptor we that and are ligands for However, LRP1B from LRP in kinetics and in its tissue expression studies on its physiological and roles as as the on its predicted amino acid LRP1B is a new member of the low density lipoprotein receptor gene family with a size (∼600 kDa) similar to that of LRP and LRP1B is more closely related to LRP than to at the amino acid and in its domain structural Fig. 1). These structural suggest that the ligands of the as as the function of the studies have of LRP1B and LRP. have that is expressed at the cell surface and is by the furin within the the cell and each of the four LRP ligands and the of each of these ligands to as it to these LRP1B and LRP in two the kinetics of ligand endocytosis determined with are distinctly different these two and similar for ligand and of ligand the internalization and is for mLRP1B4. The of internalization is more than for which in by the at the cell The physiological of this is the of LRP1B as a protein receptor internalization for cell surface LRP1B found to play a in because other members of this receptor family have found to play a in (2Howell B.W. Herz J. Curr. Opin. Neurobiol. 2001; 11: 74-81Crossref PubMed Scopus (68) Google Scholar). the within the of LRP and LRP1B is the acid in the of with proteins and thus a for the internalization of studies similar to those that have the within the of LRP and apolipoprotein E Herz J. J. J. 2000; PubMed Scopus Google Scholar, J. J. Herz J. J. 2000; PubMed Scopus Google this the expression of LRP, LRP1B, and other family members LRP is expressed in brain, and In LRP is a receptor for of and J. PubMed Scopus Google Scholar), in LRP an in growth J. G. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: PubMed Scopus Google Scholar, G. J. PubMed Scopus Google and is in the of disease P.G. Strickland D.K. J. Clin. Invest. 2000; 106: 1077-1079Crossref PubMed Scopus (38) Google and J. G. J. 2000; PubMed Google Scholar). is expressed in with expression in lung and In it as an receptor of and other A. Herz J. PubMed Scopus Google Scholar). LRP1B is expressed in brain, thyroid, and salivary a from those of the other of the gene family. more of LRP1B expression via with an with the it The of uPA and as ligands for LRP1B because are of the uPA one of the Sci. 2000; PubMed Scopus Google Scholar, P. Cancer Res. 2000; PubMed Google Scholar). The uPA a in cancer and as as other physiological and in tissue the that a of the uPA in cell and independent from its is the and other cell surface and Sci. 2000; PubMed Scopus Google Scholar, P. Cancer Res. 2000; PubMed Google Scholar). LRP is recognized as one of and function A. J. J. PubMed Google Scholar, J. Strickland D.K. J. PubMed Google Scholar, A. J. J. 1995; PubMed Scopus Google Scholar, A. J. EMBO J. PubMed Scopus Google Scholar, A. J. J. PubMed Scopus Google Scholar, Strickland D.K. J. PubMed Scopus Google Scholar, J. Sci. 2000; PubMed Google Scholar). to cell surface with high and is uPA the of the plasminogen to which in the degradation of including uPA by with the of a The to LRP with high and is with the ligand to for and LRP to the cell surface A. J. J. 1995; PubMed Scopus Google Scholar, A. J. EMBO J. PubMed Scopus Google Scholar). similar of LRP1B and its to LRP1B was via its homozygous deletions in human cancer cell lines and thus a candidate tumor suppressor. analysis that it was frequently inactivated in cell lines of human lung cancer (4Liu C.-X. Musco S. Lisitsina N.M. Fogacs E. Minna J.D. Lisitsyn N.A. Cancer Res. 2000; 60: 1961-1967PubMed Google Scholar). which that LRP1B with uPA and studies on the function of LRP1B in the function of the and in tumor In using LRP1B minireceptor we that and are ligands for However, LRP1B from LRP in kinetics and in its tissue expression studies on its physiological and roles as as the members of for
Liu et al. (Wed,) studied this question.