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

doi:10.1074/jbc.M000955200

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*

From the Departments of ^‡Molecular Genetics and ^‖Pathology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9046 and the ^**Institute of Medical Biochemistry, Department of Molecular Genetics, Biocenter and University of Vienna, A-1030 Vienna, Austria

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.

Footnotes

↵* This work was supported in part by National Institutes of Health Grants HL20948 and HL63762, the Human Frontiers Science Program, the Perot Family Foundation, and the Friends of the Alzheimer's Disease Center.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
↵§ Supported by the Deutsche Forschungsgemeinschaft.
↵¶ Max-Kade Fellow during part of this work.
↵‡ Supported by Austrian Science Foundation Grants F0606, P13931, P11694, and P13940.
↵§§ Established Investigator of the American Heart Association and Parke Davis. To whom correspondence should be addressed: Dept. of Molecular Genetics, University of Texas Southwestern, 5323 Harry Hines Blvd., Dallas, TX 75390-9046. Tel.: 214-648-5633; Fax: 214-648-8804; E-mail: herz@utsw.swmed.edu.
Published, JBC Papers in Press, May 25, 2000, DOI 10.1074/jbc.M000955200
↵2 A. Rohlmann, M. Gotthardt, and J. Herz, unpublished observations.
Abbreviations:

LDL

low density lipoprotein

apoE

apolipoprotein E

apoER2

apoE receptor-2

APP

amyloid precursor protein

GST

glutathione-S-transferase

JNK

c-Jun N-terminal kinase

LRP

LDL receptor-related protein

MAP kinase

mitogen activated protein kinase

PBS

phosphate buffered saline

PID

protein interaction domain

PTB

phosphotyrosine binding

RGS

regulation of G-protein signaling

VLDL

very low density lipoprotein

PCR

polymerase chain reaction

nNOS

neuronal nitric-oxide synthase

CHO

Chinese hamster ovary
- Received February 6, 2000.
- Revision received May 15, 2000.
The American Society for Biochemistry and Molecular Biology, Inc.