Phosphatidylinositol 3-kinase interacts with the adaptor protein Dab1 in response to reelin signaling and is required for normal cortical lamination

Hans H. Bock, Yves Jossin, Pingsheng Liu, Eckart Förster, Petra May, André M. Goffinet, Joachim Herz

Research output: Contribution to journalArticle

156 Citations (Scopus)

Abstract

Reelin is a large secreted signaling protein that binds to two members of the low density lipoprotein receptor family, the apolipoprotein E receptor 2 and the very low density lipoprotein receptor, and regulates neuronal positioning during brain development. Reelin signaling requires activation of Src family kinases as well as tyrosine phosphorylation of the intracellular adaptor protein Disabled-1 (Dab1). This results in activation of phosphatidylinositol 3-kinase (PI3K), the serine/threonine kinase Akt, and the inhibition of glycogen synthase kinase 3β, a protein that is implicated in the regulation of axonal transport. Here we demonstrate that PI3K activation by Reelin requires Src family kinase activity and depends on the Reelin-triggered interaction of Dab1 with the PI3K regulatory subunit p85α. Because the Dab1 phosphotyrosine binding domain can interact simultaneously with membrane lipids and with the intracellular domains of apolipoprotein E receptor 2 and very low density lipoprotein receptor, Dab1 is preferentially recruited to the neuronal plasma membrane, where it is phosphorylated. Efficient Dab1 phosphorylation and activation of the Reelin signaling cascade is impaired by cholesterol depletion of the plasma membrane. Using a neuronal migration assay, we also show that PI3K signaling is required for the formation of a normal cortical plate, a step that is dependent upon Reelin signaling.

Original languageEnglish (US)
Pages (from-to)38772-38779
Number of pages8
JournalJournal of Biological Chemistry
Volume278
Issue number40
DOIs
StatePublished - Oct 3 2003

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Phosphatidylinositol 3-Kinase
Chemical activation
src-Family Kinases
Phosphorylation
Cell membranes
Proteins
Cell Membrane
Glycogen Synthase Kinase 3
Phosphotyrosine
Axonal Transport
LDL Receptors
Protein-Serine-Threonine Kinases
Membrane Lipids
Cerebral Cortex
Tyrosine
Cholesterol
Assays
Brain
VLDL receptor
low density lipoprotein receptor-related protein 8

ASJC Scopus subject areas

  • Biochemistry

Cite this

Phosphatidylinositol 3-kinase interacts with the adaptor protein Dab1 in response to reelin signaling and is required for normal cortical lamination. / Bock, Hans H.; Jossin, Yves; Liu, Pingsheng; Förster, Eckart; May, Petra; Goffinet, André M.; Herz, Joachim.

In: Journal of Biological Chemistry, Vol. 278, No. 40, 03.10.2003, p. 38772-38779.

Research output: Contribution to journalArticle

Bock, Hans H. ; Jossin, Yves ; Liu, Pingsheng ; Förster, Eckart ; May, Petra ; Goffinet, André M. ; Herz, Joachim. / Phosphatidylinositol 3-kinase interacts with the adaptor protein Dab1 in response to reelin signaling and is required for normal cortical lamination. In: Journal of Biological Chemistry. 2003 ; Vol. 278, No. 40. pp. 38772-38779.
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