Microtubule Binding to Smads May Regulate TGF Beta Activity

Mol Cell. 2000 Jan;5(1):27-34. doi: 10.1016/s1097-2765(00)80400-1.

Abstract

Smad proteins are intracellular signaling effectors of the TGF beta superfamily. We show that endogenous Smad2, 3, and 4 bind microtubules (MTs) in several cell lines. Binding of Smads to MTs does not require TGF beta stimulation. TGF beta triggers dissociation from MTs, phosphorylation, and nuclear translocation of Smad2 and 3, with consequent activation of transcription in CCL64 cells. Destabilization of the MT network by nocodazole, colchicine, or a tubulin mutant disrupts the complex between Smads and MTs and increases TGF beta-induced Smad2 phosphorylation and transcriptional response in CCL64 cells. These data demonstrate that MTs may serve as a cytoplasmic sequestering network for Smads, controlling Smad2 association with and phosphorylation by activated TGF beta receptor I, and suggest a novel mechanism for the MT network to negatively regulate TGF beta function.

Publication types

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

MeSH terms

  • Activin Receptors, Type I*
  • Animals
  • Aorta
  • Cell Line
  • Cells, Cultured
  • Coronary Vessels
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Endothelium, Vascular / cytology
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / physiology*
  • Gene Expression Regulation
  • HeLa Cells
  • Humans
  • Mice
  • Microtubules / physiology*
  • Microtubules / ultrastructure
  • Nocodazole / pharmacology
  • Oligodeoxyribonucleotides, Antisense / pharmacology
  • Paclitaxel / pharmacology
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / physiology*
  • Receptor, Transforming Growth Factor-beta Type I
  • Receptors, Transforming Growth Factor beta / physiology*
  • Signal Transduction
  • Smad2 Protein
  • Smad3 Protein
  • Smad4 Protein
  • Trans-Activators / genetics
  • Trans-Activators / metabolism*
  • Transcription, Genetic / drug effects
  • Transforming Growth Factor beta / pharmacology
  • Transforming Growth Factor beta / physiology*

Substances

  • DNA-Binding Proteins
  • Oligodeoxyribonucleotides, Antisense
  • Receptors, Transforming Growth Factor beta
  • SMAD2 protein, human
  • SMAD3 protein, human
  • SMAD4 protein, human
  • Smad2 Protein
  • Smad2 protein, mouse
  • Smad3 Protein
  • Smad3 protein, mouse
  • Smad4 Protein
  • Smad4 protein, mouse
  • Trans-Activators
  • Transforming Growth Factor beta
  • Protein-Serine-Threonine Kinases
  • Activin Receptors, Type I
  • Receptor, Transforming Growth Factor-beta Type I
  • Paclitaxel
  • Nocodazole