LRP: a multifunctional scavenger and signaling receptor.

The LDL receptor–related protein (LRP) is larger than but structurally similar to other members of the LDL receptor gene family, an ancient family of endocytic receptors (1–3). Whereas the LDL receptor, the founding member of this family, appears to act solely in lipoprotein metabolism, the LRP and other members of this family appear to have other distinct functions. In this article, we will focus on the diverse biological roles of the LRP, which include functions in lipid metabolism, and also in the homeostasis of proteinases and proteinase inhibitors, cellular entry of viruses and toxins, activation of lysosomal enzymes, cellular signal transduction, and neurotransmission.

[1]  C. López-Otín,et al.  Collagenase-3 Binds to a Specific Receptor and Requires the Low Density Lipoprotein Receptor-related Protein for Internalization* , 1999, The Journal of Biological Chemistry.

[2]  D. Strickland,et al.  The alpha 2-macroglobulin receptor/low density lipoprotein receptor-related protein binds and internalizes Pseudomonas exotoxin A. , 1992, The Journal of biological chemistry.

[3]  P. Bornstein,et al.  The Low Density Lipoprotein Receptor-related Protein Modulates Levels of Matrix Metalloproteinase 9 (MMP-9) by Mediating Its Cellular Catabolism* , 2001, The Journal of Biological Chemistry.

[4]  Alain Buisson,et al.  The proteolytic activity of tissue-plasminogen activator enhances NMDA receptor-mediated signaling , 2001, Nature Medicine.

[5]  D. Holtzman,et al.  Clearance of Alzheimer's amyloid-ss(1-40) peptide from brain by LDL receptor-related protein-1 at the blood-brain barrier. , 2000, The Journal of clinical investigation.

[6]  J. Borg,et al.  Interaction of Cytosolic Adaptor Proteins with Neuronal Apolipoprotein E Receptors and the Amyloid Precursor Protein* , 1998, The Journal of Biological Chemistry.

[7]  Donna J. Webb,et al.  Urokinase-type Plasminogen Activator Stimulates the Ras/Extracellular Signal-regulated Kinase (ERK) Signaling Pathway and MCF-7 Cell Migration by a Mechanism That Requires Focal Adhesion Kinase, Src, and Shc , 2000, The Journal of Biological Chemistry.

[8]  M. Tyers,et al.  Tyrosine-phosphorylated Low Density Lipoprotein Receptor-related Protein 1 (LRP1) Associates with the Adaptor Protein SHC in SRC-transformed Cells* , 2001, The Journal of Biological Chemistry.

[9]  R. Katzman.,et al.  Modulation of amyloid beta-protein clearance and Alzheimer's disease susceptibility by the LDL receptor-related protein pathway. , 2000, The Journal of clinical investigation.

[10]  P. Bornstein,et al.  Extracellular MMP2 levels are regulated by the LRP scavenger recept thrombospondin 2. , 2000 .

[11]  B. Hyman,et al.  The endocytic receptor protein LRP also mediates neuronal calcium signaling via N-methyl-D-aspartate receptors. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[12]  K. Orth,et al.  Molecular dissection of ligand binding sites on the low density lipoprotein receptor-related protein. , 1994, The Journal of biological chemistry.

[13]  T. Willnow,et al.  Lipoprotein receptors: new roles for ancient proteins , 1999, Nature Cell Biology.

[14]  M. Stearns,et al.  Decreased expression of the low density lipoprotein receptor-related protein/alpha 2-macroglobulin receptor in invasive cell clones derived from human prostate and breast tumor cells. , 1994, Oncology research.

[15]  J. Richardson,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* , 2000, The Journal of Biological Chemistry.

[16]  W. Schneider,et al.  Cellular uptake of saposin (SAP) precursor and lysosomal delivery by the low density lipoprotein receptor‐related protein (LRP) , 1998, The EMBO journal.

[17]  E. Kandel,et al.  Mice lacking the gene encoding tissue-type plasminogen activator show a selective interference with late-phase long-term potentiation in both Schaffer collateral and mossy fiber pathways. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[18]  T. Russo,et al.  Fe65L2: a new member of the Fe65 protein family interacting with the intracellular domain of the Alzheimer's beta-amyloid precursor protein. , 1998, The Biochemical journal.

[19]  T. Springer,et al.  An extracellular beta-propeller module predicted in lipoprotein and scavenger receptors, tyrosine kinases, epidermal growth factor precursor, and extracellular matrix components. , 1998, Journal of molecular biology.

[20]  R. Tanzi,et al.  Uptake of HIV-1 Tat protein mediated by low-density lipoprotein receptor-related protein disrupts the neuronal metabolic balance of the receptor ligands , 2000, Nature Medicine.

[21]  R. Sakthivel,et al.  The Low Density Lipoprotein Receptor-related Protein/α2-Macroglobulin Receptor Regulates Cell Surface Plasminogen Activator Activity on Human Trophoblast Cells* , 1998, The Journal of Biological Chemistry.

[22]  S. Armstrong,et al.  Functional expression of low density lipoprotein receptor-related protein is controlled by receptor-associated protein in vivo. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[23]  B. Hyman,et al.  Modulation of beta-amyloid precursor protein processing by the low density lipoprotein receptor-related protein (LRP). Evidence that LRP contributes to the pathogenesis of Alzheimer's disease. , 2000, The Journal of biological chemistry.

[24]  B. Strooper,et al.  Cholesterol depletion inhibits the generation of beta-amyloid in hippocampal neurons. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[25]  W. Schneider,et al.  The Reelin Receptor ApoER2 Recruits JNK-interacting Proteins-1 and -2* , 2000, The Journal of Biological Chemistry.

[26]  M. Sudol,et al.  The WW Domain of Neural Protein FE65 Interacts with Proline-rich Motifs in Mena, the Mammalian Homolog of DrosophilaEnabled* , 1997, The Journal of Biological Chemistry.

[27]  A. V. van Zonneveld,et al.  The Second and Fourth Cluster of Class A Cysteine-rich Repeats of the Low Density Lipoprotein Receptor-related Protein Share Ligand-binding Properties* , 1999, The Journal of Biological Chemistry.

[28]  S. Moestrup,et al.  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. , 1992, The Journal of biological chemistry.

[29]  R. Muschel,et al.  The effect of E1A transfection on MMP‐9 expression and metastatic potential , 1995, International journal of cancer.

[30]  P. Gettins,et al.  NMR Solution Structure of Complement-like Repeat CR8 from the Low Density Lipoprotein Receptor-related Protein* , 1999, The Journal of Biological Chemistry.

[31]  S. E. Brodie.  New York, New York, USA , 1996 .

[32]  B. Hyman,et al.  LDL receptor-related protein, a multifunctional ApoE receptor, binds secreted β-amyloid precursor protein and mediates its degradation , 1995, Cell.

[33]  J. Buxbaum,et al.  Interaction of the Phosphotyrosine Interaction/Phosphotyrosine Binding-related Domains of Fe65 with Wild-type and Mutant Alzheimer's β-Amyloid Precursor Proteins* , 1997, The Journal of Biological Chemistry.

[34]  T. Farag,et al.  Familial hypercholesterolemia. , 1988, Journal of the Royal Society of Medicine.

[35]  R. Hammer,et al.  Inducible inactivation of hepatic LRP gene by cre-mediated recombination confirms role of LRP in clearance of chylomicron remnants. , 1998, The Journal of clinical investigation.

[36]  L. Thal,et al.  Genetic association of the low-density lipoprotein receptor-related protein gene (LRP), and apolipoprotein E receptor, with late-onset Alzheimer's disease , 1997, Neurology.

[37]  M. Brown,et al.  NPXY, a sequence often found in cytoplasmic tails, is required for coated pit-mediated internalization of the low density lipoprotein receptor. , 1990, The Journal of biological chemistry.

[38]  E. Kuechler,et al.  Members of the low density lipoprotein receptor family mediate cell entry of a minor-group common cold virus. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[39]  K. Almholt,et al.  Cancer invasion and tissue remodeling: common themes in proteolytic matrix degradation. , 1998, Current opinion in cell biology.

[40]  R. Hammer,et al.  LDL receptor-related protein internalizes and degrades uPA-PAI-1 complexes and is essential for embryo implantation , 1992, Cell.

[41]  D. Holtzman,et al.  Role of Tissue Plasminogen Activator Receptor LRP in Hippocampal Long-Term Potentiation , 2000, The Journal of Neuroscience.

[42]  S. Bressler,et al.  cDNA cloning and chromosome mapping of the human Fe65 gene: interaction of the conserved cytoplasmic domains of the human beta-amyloid precursor protein and its homologues with the mouse Fe65 protein. , 1996, Human molecular genetics.

[43]  H. Harper,et al.  Urokinase receptor (CD87) aggregation triggers phosphoinositide hydrolysis and intracellular calcium mobilization in mononuclear phagocytes. , 1999, Journal of immunology.

[44]  P. Moore,et al.  Virus-specific Activation of a Novel Interferon Regulatory Factor, IRF-5, Results in the Induction of Distinct Interferon α Genes* , 2001, The Journal of Biological Chemistry.

[45]  Steingrimur Stefansson,et al.  The serpin PAI-1 inhibits cell migration by blocking integrin αvβ3 binding to vitronectin , 1996, Nature.

[46]  D. Lawrence,et al.  The serpin PAI-1 inhibits cell migration by blocking integrin alpha V beta 3 binding to vitronectin. , 1996, Nature.

[47]  John Shelton,et al.  Reeler/Disabled-like Disruption of Neuronal Migration in Knockout Mice Lacking the VLDL Receptor and ApoE Receptor 2 , 1999, Cell.

[48]  K. Sandhoff,et al.  Sphingolipid Metabolism: Sphingoid Analogs, Sphingolipid Activator Proteins, and the Pathology of the Cell a , 1998 .

[49]  Joachim Herz,et al.  Apolipoprotein E receptors: linking brain development and alzheimer's disease , 2000, Nature Reviews Neuroscience.

[50]  G. Bengtsson-Olivecrona,et al.  Lipoprotein lipase enhances the binding of chylomicrons to low density lipoprotein receptor-related protein. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[51]  T. Willnow,et al.  Inhibition of hepatic chylomicron remnant uptake by gene transfer of a receptor antagonist. , 1994, Science.

[52]  H. Yoo.  Growth Hormone Deficiency Associated with Pituitary Stalk Interruption Syndrome , 1998, Hormone Research in Paediatrics.