Apolipoprotein E receptors are required for reelin-induced proteasomal degradation of the neuronal adaptor protein disabled-1

Hans H. Bock, Yves Jossin, Petra May, Oliver Bergner, Joachim Herz

Research output: Contribution to journalArticle

80 Citations (Scopus)

Abstract

The cytoplasmic adaptor protein Disabled-1 (Dab1) is necessary for the regulation of neuronal positioning in the developing brain by the secreted molecule Reelin. Binding of Reelin to the neuronal apolipoprotein E receptors apoER2 and very low density lipoprotein receptor induces tyrosine phosphorylation of Dab1 and the subsequent activation or relocalization of downstream targets like phosphatidylinositol 3 (PI3)-kinase and Nckβ. Disruption of Reelin signaling leads to the accumulation of Dab1 protein in the brains of genetically modified mice, suggesting that Reelin limits its own action in responsive neurons by down-regulating the levels of Dab1 expression. Here, we use cultured primary embryonic neurons as a model to demonstrate that Reelin treatment targets Dab1 for proteolytic degradation by the ubiquitin-proteasome pathway. We show that tyrosine phosphorylation of Dab1 but not PI3-kinase activation is required for its proteasomal targeting. Genetic deficiency in the Dab1 kinase Fyn prevents Dab1 degradation. The Reelin-induced Dabl degradation also depends on apoER2 and very low density lipoprotein receptor in a gene-dose dependent manner. Moreover, pharmacological blockade of the proteasome prevents the formation of a proper cortical plate in an in vitro slice culture assay. Our results demonstrate that signaling through neuronal apoE receptors can activate the ubiquitin-proteasome machinery, which might have implications for the role of Reelin during neurodevelopment and in the regulation of synaptic transmission.

Original languageEnglish (US)
Pages (from-to)33471-33479
Number of pages9
JournalJournal of Biological Chemistry
Volume279
Issue number32
DOIs
StatePublished - Aug 6 2004

Fingerprint

Low Density Lipoprotein Receptor-Related Protein-1
Proteasome Endopeptidase Complex
Phosphatidylinositol 3-Kinase
Phosphorylation
Ubiquitin
Degradation
Neurons
Tyrosine
Brain
Chemical activation
Proteins
Synaptic Transmission
Cerebral Cortex
Machinery
Assays
Phosphotransferases
Genes
Pharmacology
Molecules
VLDL receptor

ASJC Scopus subject areas

  • Biochemistry

Cite this

Apolipoprotein E receptors are required for reelin-induced proteasomal degradation of the neuronal adaptor protein disabled-1. / Bock, Hans H.; Jossin, Yves; May, Petra; Bergner, Oliver; Herz, Joachim.

In: Journal of Biological Chemistry, Vol. 279, No. 32, 06.08.2004, p. 33471-33479.

Research output: Contribution to journalArticle

@article{020f1e83893d4d9ba2706d9ec4c4fb4b,
title = "Apolipoprotein E receptors are required for reelin-induced proteasomal degradation of the neuronal adaptor protein disabled-1",
abstract = "The cytoplasmic adaptor protein Disabled-1 (Dab1) is necessary for the regulation of neuronal positioning in the developing brain by the secreted molecule Reelin. Binding of Reelin to the neuronal apolipoprotein E receptors apoER2 and very low density lipoprotein receptor induces tyrosine phosphorylation of Dab1 and the subsequent activation or relocalization of downstream targets like phosphatidylinositol 3 (PI3)-kinase and Nckβ. Disruption of Reelin signaling leads to the accumulation of Dab1 protein in the brains of genetically modified mice, suggesting that Reelin limits its own action in responsive neurons by down-regulating the levels of Dab1 expression. Here, we use cultured primary embryonic neurons as a model to demonstrate that Reelin treatment targets Dab1 for proteolytic degradation by the ubiquitin-proteasome pathway. We show that tyrosine phosphorylation of Dab1 but not PI3-kinase activation is required for its proteasomal targeting. Genetic deficiency in the Dab1 kinase Fyn prevents Dab1 degradation. The Reelin-induced Dabl degradation also depends on apoER2 and very low density lipoprotein receptor in a gene-dose dependent manner. Moreover, pharmacological blockade of the proteasome prevents the formation of a proper cortical plate in an in vitro slice culture assay. Our results demonstrate that signaling through neuronal apoE receptors can activate the ubiquitin-proteasome machinery, which might have implications for the role of Reelin during neurodevelopment and in the regulation of synaptic transmission.",
author = "Bock, {Hans H.} and Yves Jossin and Petra May and Oliver Bergner and Joachim Herz",
year = "2004",
month = "8",
day = "6",
doi = "10.1074/jbc.M401770200",
language = "English (US)",
volume = "279",
pages = "33471--33479",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "32",

}

TY - JOUR

T1 - Apolipoprotein E receptors are required for reelin-induced proteasomal degradation of the neuronal adaptor protein disabled-1

AU - Bock, Hans H.

AU - Jossin, Yves

AU - May, Petra

AU - Bergner, Oliver

AU - Herz, Joachim

PY - 2004/8/6

Y1 - 2004/8/6

N2 - The cytoplasmic adaptor protein Disabled-1 (Dab1) is necessary for the regulation of neuronal positioning in the developing brain by the secreted molecule Reelin. Binding of Reelin to the neuronal apolipoprotein E receptors apoER2 and very low density lipoprotein receptor induces tyrosine phosphorylation of Dab1 and the subsequent activation or relocalization of downstream targets like phosphatidylinositol 3 (PI3)-kinase and Nckβ. Disruption of Reelin signaling leads to the accumulation of Dab1 protein in the brains of genetically modified mice, suggesting that Reelin limits its own action in responsive neurons by down-regulating the levels of Dab1 expression. Here, we use cultured primary embryonic neurons as a model to demonstrate that Reelin treatment targets Dab1 for proteolytic degradation by the ubiquitin-proteasome pathway. We show that tyrosine phosphorylation of Dab1 but not PI3-kinase activation is required for its proteasomal targeting. Genetic deficiency in the Dab1 kinase Fyn prevents Dab1 degradation. The Reelin-induced Dabl degradation also depends on apoER2 and very low density lipoprotein receptor in a gene-dose dependent manner. Moreover, pharmacological blockade of the proteasome prevents the formation of a proper cortical plate in an in vitro slice culture assay. Our results demonstrate that signaling through neuronal apoE receptors can activate the ubiquitin-proteasome machinery, which might have implications for the role of Reelin during neurodevelopment and in the regulation of synaptic transmission.

AB - The cytoplasmic adaptor protein Disabled-1 (Dab1) is necessary for the regulation of neuronal positioning in the developing brain by the secreted molecule Reelin. Binding of Reelin to the neuronal apolipoprotein E receptors apoER2 and very low density lipoprotein receptor induces tyrosine phosphorylation of Dab1 and the subsequent activation or relocalization of downstream targets like phosphatidylinositol 3 (PI3)-kinase and Nckβ. Disruption of Reelin signaling leads to the accumulation of Dab1 protein in the brains of genetically modified mice, suggesting that Reelin limits its own action in responsive neurons by down-regulating the levels of Dab1 expression. Here, we use cultured primary embryonic neurons as a model to demonstrate that Reelin treatment targets Dab1 for proteolytic degradation by the ubiquitin-proteasome pathway. We show that tyrosine phosphorylation of Dab1 but not PI3-kinase activation is required for its proteasomal targeting. Genetic deficiency in the Dab1 kinase Fyn prevents Dab1 degradation. The Reelin-induced Dabl degradation also depends on apoER2 and very low density lipoprotein receptor in a gene-dose dependent manner. Moreover, pharmacological blockade of the proteasome prevents the formation of a proper cortical plate in an in vitro slice culture assay. Our results demonstrate that signaling through neuronal apoE receptors can activate the ubiquitin-proteasome machinery, which might have implications for the role of Reelin during neurodevelopment and in the regulation of synaptic transmission.

UR - http://www.scopus.com/inward/record.url?scp=4043068564&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=4043068564&partnerID=8YFLogxK

U2 - 10.1074/jbc.M401770200

DO - 10.1074/jbc.M401770200

M3 - Article

C2 - 15175346

AN - SCOPUS:4043068564

VL - 279

SP - 33471

EP - 33479

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 32

ER -