TGF-beta-mediated phosphorylation of hnRNP E1 induces EMT via transcript-selective translational induction of Dab2 and ILEI

Nat Cell Biol. 2010 Mar;12(3):286-93. doi: 10.1038/ncb2029. Epub 2010 Feb 14.

Abstract

Transforming growth factor-beta (TGF-beta) induces epithelial-mesenchymal transdifferentiation (EMT) accompanied by cellular differentiation and migration. Despite extensive transcriptomic profiling, the identification of TGF-beta-inducible, EMT-specific genes has met with limited success. Here we identify a post-transcriptional pathway by which TGF-beta modulates the expression of EMT-specific proteins and of EMT itself. We show that heterogeneous nuclear ribonucleoprotein E1 (hnRNP E1) binds a structural, 33-nucleotide TGF-beta-activated translation (BAT) element in the 3' untranslated region of disabled-2 (Dab2) and interleukin-like EMT inducer (ILEI) transcripts, and represses their translation. TGF-beta activation leads to phosphorylation at Ser 43 of hnRNP E1 by protein kinase Bbeta/Akt2, inducing its release from the BAT element and translational activation of Dab2 and ILEI messenger RNAs. Modulation of hnRNP E1 expression or its post-translational modification alters the TGF-beta-mediated reversal of translational silencing of the target transcripts and EMT. These results suggest the existence of a TGF-beta-inducible post-transcriptional regulon that controls EMT during the development and metastatic progression of tumours.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions / physiology
  • Adaptor Proteins, Signal Transducing
  • Adaptor Proteins, Vesicular Transport / genetics
  • Adaptor Proteins, Vesicular Transport / metabolism*
  • Animals
  • Apoptosis Regulatory Proteins
  • Cadherins / metabolism
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cell Line, Transformed
  • Cell Transdifferentiation / physiology*
  • Cytokines / genetics
  • Cytokines / metabolism*
  • DNA-Binding Proteins
  • Epithelial Cells / pathology
  • Female
  • Gene Expression / drug effects
  • Gene Expression / genetics
  • Gene Expression Regulation, Neoplastic / physiology*
  • Insulin / pharmacology
  • Mammary Glands, Animal / pathology
  • Mesoderm / pathology
  • Mice
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • Phosphorylation / drug effects
  • Phosphorylation / physiology
  • Polyribosomes / metabolism
  • Protein Binding / genetics
  • Protein Biosynthesis / physiology
  • Protein Isoforms / metabolism
  • Protein Kinase Inhibitors / pharmacology
  • Proto-Oncogene Proteins c-akt / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • RNA, Small Interfering / genetics
  • RNA-Binding Proteins
  • Signal Transduction / drug effects
  • Transforming Growth Factor beta / pharmacology*
  • Vimentin / metabolism

Substances

  • 3' Untranslated Regions
  • Adaptor Proteins, Signal Transducing
  • Adaptor Proteins, Vesicular Transport
  • Apoptosis Regulatory Proteins
  • Cadherins
  • Carrier Proteins
  • Cdh2 protein, mouse
  • Cytokines
  • DNA-Binding Proteins
  • Dab2 protein, mouse
  • Fam3c protein, mouse
  • Insulin
  • Neoplasm Proteins
  • Pcbp1 protein, mouse
  • Protein Isoforms
  • Protein Kinase Inhibitors
  • RNA, Messenger
  • RNA, Small Interfering
  • RNA-Binding Proteins
  • Transforming Growth Factor beta
  • Vimentin
  • Akt2 protein, mouse
  • Proto-Oncogene Proteins c-akt