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
ABSTRACT The members of the low density lipoprotein (LDL) receptor gene family bind a broad spectrum of extracellular ligands. Traditionally, they had been regarded as mere cargo receptors that promote the endocytosis and lysosomal delivery of these ligands. However, recent genetic experiments in mice have revealed critical functions for two LDL receptor family members, the very low density lipoprotein receptor and the apoE receptor-2, in the transmission of extracellular signals and the activation of intracellular tyrosine kinases. This process regulates neuronal migration and is crucial for brain development. Signaling through these receptors requires the interaction of their cytoplasmic tails with the intracellular adaptor protein Disabled-1 (DAB1). Here, we identify an extended set of cytoplasmic proteins that might also participate in signal transmission by the LDL receptor gene family. Most of these novel proteins are adaptor or scaffold proteins that contain PID or PDZ domains and function in the regulation of mitogen-activated protein kinases, cell adhesion, vesicle trafficking, or neurotransmission. We show that binding of DAB1 interferes with receptor internalization suggesting a mechanism by which signaling through this class of receptors might be regulated. Taken together, these findings imply much broader physiological functions for the LDL receptor family than had previously been appreciated. They form the basis for the elucidation of the molecular pathways by which cells respond to the diversity of ligands that bind to these multifunctional receptors on the cell surface.
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ABSTRACT: Abstract: The central nervous system (CNS) barriers are composed of blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier (B-CSFB). The BBB and B-CSFB are a highly specialized brain endothelial and epithelial structure of the fully differentiated neurovascular system. These barriers separate components of the circulating blood from neurons. Moreover, the BBB and B-CSFB maintain the chemical composition of the neuronal "milieu," which is required for the proper functioning of neuronal circuits, synaptic transmission, synaptic remodelling, angiogenesis, and neurogenesis in the adult brain. Hematoencephalic barrier breakdown, due to disruption of the tight junctions, alters transport of molecules between blood and brain and vice versa, causes an aberrant angiogenesis, vessel regression, and inflammatory responses. Megalin is a multi-ligand endocytic receptor expressed in the choroid plexus epithelium and in the brain-endothelial cells, playing a central role in the clearance/entrance of many proteins from the brain or cerebrospinal fluid (CSF). Megalin cooperates with various membrane molecules and interacts with many adaptor proteins for endocytic trafficking. It has already been implicated in amyloid- clearance and amyloidosis through the BBB and B-CSFB. Also, it is a promiscuous receptor involved in the endocytic uptake of many ligands, including many of the known carriers of amyloid-, insulin, IGF-I, leptin, transthyretin, transferrin, ApoE and others. The knowledge of B-CSFB and its transporters in healthy and pathological situations supports the development of new therapeutic approaches for chronic diseases such as Alzheimer's, Parkinson's, amyotrophic lateral sclerosis, multiple sclerosis, brain cancer, diabetes and others. This article outlines recent patents on artificial carriers for transport of substances across of the CNS barriers, different models for the drug delivery research and future therapies for the treatment of Alzheimer’s disease.Recent Patents on Endocrine Metabolic & Immune Drug Discovery 11/2010; 4:1. DOI:10.2174/1872214811004030190
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ABSTRACT: Apolipoprotein E (apoE)-induced activation of low-density lipoprotein receptor (LDL) family members reduces inflammatory responses by suppressing c-Jun N-terminal kinase (JNK) activation. We aimed to identify which specific receptor family member mediates the effect of apoE on inflammation in primary cultures of microglia. Low-density lipoprotein receptor-related protein 1 (LRP1)-deficient (LRP1-/-) microglia were derived from mice using tissue-specific loxP/Cre recombination. Using a peptide formed from the receptor-binding region of apoE (EP), we found that LRP1 mediates the effects of apoE on microglial inflammation. Microglial LRP1 was also essential for EP to suppress JNK activation induced by lipopolysaccharide.Journal of neuroimmunology 08/2009; 214(1-2):25-32. DOI:10.1016/j.jneuroim.2009.06.010 · 2.79 Impact Factor
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ABSTRACT: Numerous proteins involved in endocytosis at the plasma membrane have been shown to be present at novel intracellular locations and to have previously unrecognized functions. ARH (autosomal recessive hypercholesterolemia) is an endocytic clathrin-associated adaptor protein that sorts members of the LDL receptor superfamily (LDLR, megalin, LRP). We report here that ARH also associates with centrosomes in several cell types. ARH interacts with centrosomal (gamma-tubulin and GPC2 and GPC3) and motor (dynein heavy and intermediate chains) proteins. ARH cofractionates with gamma-tubulin on isolated centrosomes, and gamma-tubulin and ARH interact on isolated membrane vesicles. During mitosis, ARH sequentially localizes to the nuclear membrane, kinetochores, spindle poles and the midbody. Arh(-/-) embryonic fibroblasts (MEFs) show smaller or absent centrosomes suggesting ARH plays a role in centrosome assembly. Rat-1 fibroblasts depleted of ARH by siRNA and Arh(-/-) MEFs exhibit a slower rate of growth and prolonged cytokinesis. Taken together the data suggest that the defects in centrosome assembly in ARH depleted cells may give rise to cell cycle and mitotic/cytokinesis defects. We propose that ARH participates in centrosomal and mitotic dynamics by interacting with centrosomal proteins. Whether the centrosomal and mitotic functions of ARH are related to its endocytic role remains to be established.Molecular biology of the cell 08/2008; 19(7):2949-61. DOI:10.1091/mbc.E07-05-0521 · 5.98 Impact Factor