Disruption of transforming growth factor-beta signaling in ELF beta-spectrin-deficient mice

Science. 2003 Jan 24;299(5606):574-7. doi: 10.1126/science.1075994.

Abstract

Disruption of the adaptor protein ELF, a beta-spectrin, leads to disruption of transforming growth factor-beta (TGF-beta) signaling by Smad proteins in mice. Elf-/- mice exhibit a phenotype similar to smad2+/-/smad3+/- mutant mice of midgestational death due to gastrointestinal, liver, neural, and heart defects. We show that TGF-beta triggers phosphorylation and association of ELF with Smad3 and Smad4, followed by nuclear translocation. ELF deficiency results in mislocalization of Smad3 and Smad4 and loss of the TGF-beta-dependent transcriptional response, which could be rescued by overexpression of the COOH-terminal region of ELF. This study reveals an unexpected molecular link between a major dynamic scaffolding protein and a key signaling pathway.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Abnormalities, Multiple
  • Animals
  • Carrier Proteins / metabolism
  • Cell Membrane / metabolism
  • Cell Nucleus / metabolism
  • Contractile Proteins / metabolism
  • DNA-Binding Proteins / metabolism
  • Embryonic and Fetal Development
  • Filamins
  • Gene Targeting
  • Genes, fos
  • Liver / abnormalities
  • Liver / embryology
  • Liver / metabolism*
  • Mice
  • Mice, Knockout
  • Microfilament Proteins / metabolism
  • Microscopy, Confocal
  • Mutation
  • Phenotype
  • Phosphorylation
  • Platelet-Derived Growth Factor / pharmacology
  • Signal Transduction*
  • Smad2 Protein
  • Smad3 Protein
  • Smad4 Protein
  • Spectrin / genetics
  • Spectrin / metabolism*
  • Trans-Activators / metabolism
  • Transcriptional Activation
  • Transforming Growth Factor beta / metabolism*
  • Transforming Growth Factor beta / pharmacology
  • Tumor Cells, Cultured

Substances

  • Carrier Proteins
  • Contractile Proteins
  • DNA-Binding Proteins
  • Filamins
  • Microfilament Proteins
  • Platelet-Derived Growth Factor
  • Smad2 Protein
  • Smad2 protein, mouse
  • Smad3 Protein
  • Smad3 protein, mouse
  • Smad4 Protein
  • Smad4 protein, mouse
  • Trans-Activators
  • Transforming Growth Factor beta
  • Spectrin