L1 coupling to ankyrin and the spectrin-actin cytoskeleton modulates ethanol inhibition of L1 adhesion and ethanol teratogenesis

Xiaowei Dou, Carrie Menkari, Rei Mitsuyama, Tatiana Foroud, Leah Wetherill, Peter Hammond, Michael Suttie, Xiaopan Chen, Shao Yu Chen, Michael E. Charness

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Ethanol causes fetal alcohol spectrumdisorders (FASDs) partly by inhibiting cell adhesionmediated by theL1neural cell adhesionmolecule.Ethanol interactswithanalcoholbindingpocket intheL1 extracellulardomain (ECD), and dephosphorylation of S1248 in the L1 cytoplasmic domain (CD) renders L1 adhesion insensitive to inhibition by ethanol (L1 insensitive). The mechanism underlying this inside-out signaling is unknown. Here we show that phosphorylation of the human L1-CD at S1152, Y1176, S1181, and S1248 renders L1 sensitive to ethanol by promoting L1 coupling with ankyrin-G and the spectrin-actin cytoskeleton. Knockdown of ankyrin-G or L1 mutations that uncouple L1 from ankyrin reduce L1 sensitivity to ethanol, but not methanol, consistent with a small conformational change in the extracellular alcohol binding pocket. Phosphorylation of Y1176 and ankyrin-G coupling with L1 are higher in NIH/3T3 clonal cell lines in which ethanol inhibits L1 adhesion than in ethanol-resistant NIH/3T3 clonal cell lines. Similarly, phosphorylation of Y1176 is higher in C57BL/6J mice that are sensitive to ethanol teratogenesis than in ethanol resistant C57BL/6N mice. Finally, polymorphisms in genes that encode ankyrin-G and p90rsk, a kinase that phosphorylates S1152, are linked to facial dysmorphology in children with heavy prenatal ethanol exposure. These findings indicate that genes that regulate L1 coupling to ankyrin may influence susceptibility to FASD.

Original languageEnglish (US)
Pages (from-to)1364-1374
Number of pages11
JournalFASEB Journal
Volume32
Issue number3
DOIs
StatePublished - Mar 1 2018

Fingerprint

Ankyrins
Teratogenesis
Spectrin
Actin Cytoskeleton
Actins
Ethanol
Adhesion
Phosphorylation
NIH 3T3 Cells
Alcohols
Inbred C57BL Mouse
Genes
Cells
Cell Line
Polymorphism
Methanol
Phosphotransferases

Keywords

  • Alcohol
  • FASD
  • Phosphorylation
  • Susceptibility

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

Cite this

L1 coupling to ankyrin and the spectrin-actin cytoskeleton modulates ethanol inhibition of L1 adhesion and ethanol teratogenesis. / Dou, Xiaowei; Menkari, Carrie; Mitsuyama, Rei; Foroud, Tatiana; Wetherill, Leah; Hammond, Peter; Suttie, Michael; Chen, Xiaopan; Chen, Shao Yu; Charness, Michael E.

In: FASEB Journal, Vol. 32, No. 3, 01.03.2018, p. 1364-1374.

Research output: Contribution to journalArticle

Dou, X, Menkari, C, Mitsuyama, R, Foroud, T, Wetherill, L, Hammond, P, Suttie, M, Chen, X, Chen, SY & Charness, ME 2018, 'L1 coupling to ankyrin and the spectrin-actin cytoskeleton modulates ethanol inhibition of L1 adhesion and ethanol teratogenesis', FASEB Journal, vol. 32, no. 3, pp. 1364-1374. https://doi.org/10.1096/fj.201700970
Dou, Xiaowei ; Menkari, Carrie ; Mitsuyama, Rei ; Foroud, Tatiana ; Wetherill, Leah ; Hammond, Peter ; Suttie, Michael ; Chen, Xiaopan ; Chen, Shao Yu ; Charness, Michael E. / L1 coupling to ankyrin and the spectrin-actin cytoskeleton modulates ethanol inhibition of L1 adhesion and ethanol teratogenesis. In: FASEB Journal. 2018 ; Vol. 32, No. 3. pp. 1364-1374.
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AU - Dou, Xiaowei

AU - Menkari, Carrie

AU - Mitsuyama, Rei

AU - Foroud, Tatiana

AU - Wetherill, Leah

AU - Hammond, Peter

AU - Suttie, Michael

AU - Chen, Xiaopan

AU - Chen, Shao Yu

AU - Charness, Michael E.

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AB - Ethanol causes fetal alcohol spectrumdisorders (FASDs) partly by inhibiting cell adhesionmediated by theL1neural cell adhesionmolecule.Ethanol interactswithanalcoholbindingpocket intheL1 extracellulardomain (ECD), and dephosphorylation of S1248 in the L1 cytoplasmic domain (CD) renders L1 adhesion insensitive to inhibition by ethanol (L1 insensitive). The mechanism underlying this inside-out signaling is unknown. Here we show that phosphorylation of the human L1-CD at S1152, Y1176, S1181, and S1248 renders L1 sensitive to ethanol by promoting L1 coupling with ankyrin-G and the spectrin-actin cytoskeleton. Knockdown of ankyrin-G or L1 mutations that uncouple L1 from ankyrin reduce L1 sensitivity to ethanol, but not methanol, consistent with a small conformational change in the extracellular alcohol binding pocket. Phosphorylation of Y1176 and ankyrin-G coupling with L1 are higher in NIH/3T3 clonal cell lines in which ethanol inhibits L1 adhesion than in ethanol-resistant NIH/3T3 clonal cell lines. Similarly, phosphorylation of Y1176 is higher in C57BL/6J mice that are sensitive to ethanol teratogenesis than in ethanol resistant C57BL/6N mice. Finally, polymorphisms in genes that encode ankyrin-G and p90rsk, a kinase that phosphorylates S1152, are linked to facial dysmorphology in children with heavy prenatal ethanol exposure. These findings indicate that genes that regulate L1 coupling to ankyrin may influence susceptibility to FASD.

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