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

Item Type:	Article
Title:	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
Creators Name:	Gotthardt, M. and Trommsdorff, M. and Nevitt, M.F. and Shelton, J. and Richardson, J.A. and Stockinger, W. and Nimpf, J. and Herz, J.
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.
Keywords:	Amino Acid Sequence, Brain, Cell Adhesion, Cell Communication, Cultured Cells, Cytosol, DNA Primers, Endocytosis, Glutathione Transferase, In Situ Hybridization, Kidney, LDL Lipoproteins, Liver, Biological Models, Molecular Sequence Data, Multigene Family, Nerve Tissue Proteins, Plasmids, Tertiary Protein Structure, LDL Receptors, Recombinant Fusion Proteins, Amino Acid Sequence Homology, Signal Transduction, Time Factors, Two-Hybrid System Techniques, Animals, Mice
Source:	Journal of Biological Chemistry
ISSN:	0021-9258
Publisher:	American Society for Biochemistry and Molecular Biology
Volume:	275
Number:	33
Page Range:	25616-25624
Date:	18 August 2000
Official Publication:	https://doi.org/10.1074/jbc.M000955200
PubMed:	View item in PubMed

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