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

M. Gotthardt, M. Trommsdorff, M. F. Nevitt, J. Shelton, J. A. Richardson, W. Stockinger, J. Nimpf, J. Herz

Research output: Contribution to journalArticle

370 Citations (Scopus)

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 ceils respond to the diversity of ligands that bind to these multifunctional receptors on the cell surface.

Original languageEnglish (US)
Pages (from-to)25616-25624
Number of pages9
JournalJournal of Biological Chemistry
Volume275
Issue number33
DOIs
StatePublished - Aug 18 2000

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Cellular radio systems
Signal transduction
LDL Receptors
Scaffolds
Signal Transduction
Genes
Communication
Ligands
Proteins
Low Density Lipoprotein Receptor-Related Protein-1
PDZ Domains
Cell adhesion
Cell Surface Receptors
Endocytosis
Mitogen-Activated Protein Kinases
Cell Adhesion
Synaptic Transmission
Protein-Tyrosine Kinases
Tail
Brain

ASJC Scopus subject areas

  • Biochemistry

Cite this

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. / Gotthardt, M.; Trommsdorff, M.; Nevitt, M. F.; Shelton, J.; Richardson, J. A.; Stockinger, W.; Nimpf, J.; Herz, J.

In: Journal of Biological Chemistry, Vol. 275, No. 33, 18.08.2000, p. 25616-25624.

Research output: Contribution to journalArticle

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