Well, RAP stands for
receptor associated protein and the funny thing that in some places it is referred to as LRP1 agonist and in others as antagonist, and in one paper both, in different places. Regardless, I doubt that could be of any use to your grandpa.
But this LRP1 turned out an interesting character. Google gave many links to a patent that was applied for in May 2011 for "a pharmaceutical composition comprising an LRP1 receptor agonist for use in the treatment of cancer characterized by Wnt signaling pathway and for the treatment of an HIV-infection".
Here is some good info on LRP1:
http://physrev.physi...t/88/3/887.full
LRP1 Controls Intracellular Cholesterol Storage and Fatty Acid Synthesis through Modulation of Wnt Signaling
The LDL receptor-related protein (originally called LRP, but now referred to as LRP1) is a large endocytic receptor that is widely expressed in several tissues. LRP1 is a member of the LDL receptor family that plays diverse roles in various biological processes including lipoprotein metabolism, degradation of proteases, activation of lysosomal enzymes, and cellular entry of bacterial toxins and viruses. Deletion of the LRP1 gene leads to lethality in mice, revealing a critical, but as of yet, undefined role in development. Tissue-specific gene deletion studies reveal an important contribution of LRP1 in the vasculature, central nervous system, macrophages, and adipocytes. Three important properties of LRP1 dictate its diverse role in physiology: 1) its ability to recognize more than 30 distinct ligands, 2) its ability to bind a large number of cytoplasmic adaptor proteins via determinants located on its cytoplasmic domain in a phosphorylation-specific manner, and 3) its ability to associate with and modulate the activity of other transmembrane receptors such as integrins and receptor tyrosine kinases.
The low-density lipoprotein receptor-related protein 1 (LRP1) is a multifunctional cell surface receptor. Two NPXY motifs in the intracellular domain (ICD) serve as docking sites for several cytoplasmic adaptor proteins... which control intracellular trafficking, as well as signaling events. LRP1 interacts with and mediates endocytosis of more than 40 unrelated ligands ranging from viruses to protease/protease inhibitor complexes, cytokines, and growth factors. In the liver, LRP1 and the LDL receptor (LDLr) share the endocytosis and subsequent degradation of TG-rich very-low-density lipoproteins and chylomicron remnants. However, endocytosis and clearance of macromolecules is only one function of LRP1. There is now substantial evidence that LRP1 also serves as a regulator of several fundamental signal transduction pathways that are essential for cell migration, cell proliferation, and vascular remodeling. For instance, LRP1 post-translationally modulates and integrates TGFβ1 and PDGF signals in vascular smooth muscle cells (VSMC), which is essential for protecting the vessel wall from atherosclerosis. A prominent feature of atherosclerotic lesions is the accumulation of cholesterol in the vascular wall, raising the possibility that LRP1 might also physiologically modulate lipid trafficking and storage in adipocytes. Here, we show that LRP1 controls signaling pathways involved in cholesterol storage and fatty acid synthesis during adipocyte differentiation.
http://www.jbc.org/c...4/49/34045.full
Low Density Lipoprotein Receptor-related Protein 1 Promotes Anti-apoptotic Signaling in Neurons by Activating Akt Survival Pathway
The low density lipoprotein receptor-related protein 1 (LRP1) is a multi-ligand receptor abundantly expressed in neurons. Previous work has shown that brain LRP1 levels are decreased during aging and in Alzheimer disease. Although mounting evidence has demonstrated a role for LRP1 in the metabolism of apolipoprotein E/lipoprotein and amyloid-β peptide, whether LRP1 also plays a direct role in neuronal survival is not clear. Here, we show that LRP1 expression is critical for the survival of primary neurons under stress conditions including trophic withdrawal, the presence of apoptosis inducers, or amyloid-β-induced neurotoxicity. Using lentiviral short hairpin RNA to knock down endogenous LRP1 expression, we showed that a depletion of LRP1 leads to an activation of caspase-3 and increased neuronal apoptosis, an effect that was rescued by a caspase-3 inhibitor. A correlation between decreased Akt phosphorylation and the activation of caspase-3 was demonstrated in LRP1 knocked down neurons. Notably, LRP1 knockdown decreased insulin receptor levels in primary neurons, suggesting that decreased neuronal survival might be a consequence of an impaired insulin receptor signaling pathway. Correspondingly, both insulin receptor and phospho-Akt levels were decreased in LRP1 forebrain knock-out mice. These results demonstrate that LRP1 mediates anti-apoptotic function in neurons by regulating insulin receptor and the Akt survival pathway and suggest that restoring LRP1 expression in Alzheimer disease brain might be beneficial to inhibiting neurodegeneration.
Originally described as a clearance receptor for lipoproteins in the liver, the low density lipoprotein receptor-related protein 1 (LRP1)2 plays essential roles in development and mediates important tissue-specific functions throughout adulthood. These include regulation of glutamatergic synaptic transmission in the nervous system, prevention of vascular smooth muscle cell proliferation and atherosclerosis development, catabolism of activated coagulation factor VIII in hepatocytes, and regulation of body energy by adipocytes (1, 2). Mounting evidence suggests an important role for LRP1 in the pathogenesis of Alzheimer disease (AD). LRP1 regulates the production and clearance of amyloid-β (Aβ) peptide and the metabolism of several AD-associated ligands, including apolipoprotein E (apoE), which has three isoforms in humans with apoE4 being a major risk factor for late onset AD.
...In AD patients and in the elderly, brain LRP1 levels are significantly decreased and inversely correlate with the age of onset of AD, suggesting that a decrease in LRP1 functions might contribute to cognitive decline.
http://www.ncbi.nlm....ertype=abstract
Lipoprotein Receptor LRP1 Regulates Leptin Signaling and Energy Homeostasis in the Adult Central Nervous System
Here we show that the lipoprotein receptor LRP1 regulates leptin signaling and energy homeostasis. Conditional deletion of the Lrp1 gene in the brain resulted in an obese phenotype characterized by increased food intake, decreased energy consumption, and decreased leptin signaling. LRP1 directly binds to leptin and the leptin receptor complex and is required for leptin receptor phosphorylation and Stat3 activation. We further showed that deletion of the Lrp1 gene specifically in the hypothalamus by Cre lentivirus injection is sufficient to trigger accelerated weight gain. Together, our results demonstrate that the lipoprotein receptor LRP1, which is critical in lipid metabolism, also regulates food intake and energy homeostasis in the adult central nervous system.
http://webcache.goog...n&ct=clnk&gl=us
The lab also demonstrated that the increased low-density lipoprotein receptor-related protein 1 (LRP1) expression in glioblastoma promotes tumor cell migration and invasion by upregulating the expression of several metalloproteases.
The Unfolded Protein Response Is a Major Mechanism by Which LRP1 Regulates Schwann Cell Survival after Injury. 2011
And finally, wiki genes on LPR1:
http://www.wikigenes...ene/e/4035.html.
Edited by xEva, 12 March 2012 - 03:13 AM.
