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1: Mol Cell Biol. 2007 Sep;27(17):6068-83. Epub 2007 Jun 25.
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Arkadia activates Smad3/Smad4-dependent transcription by triggering signal-induced SnoN degradation.

Levy L, Howell M, Das D, Harkin S, Episkopou V, Hill CS.

Laboratory of Developmental Signalling, Cancer Research UK London Research Institute, Lincoln's Inn Fields Laboratories, 44 Lincoln's Inn Fields, London WC2A 3PX, United Kingdom.

E3 ubiquitin ligases play important roles in regulating transforming growth factor beta (TGF-beta)/Smad signaling. Screening of an E3 ubiquitin ligase small interfering RNA library, using TGF-beta induction of a Smad3/Smad4-dependent luciferase reporter as a readout, revealed that Arkadia is an E3 ubiquitin ligase that is absolutely required for this TGF-beta response. Knockdown of Arkadia or overexpression of a dominant-negative mutant completely abolishes transcription from Smad3/Smad4-dependent reporters, but not from Smad1/Smad4-dependent reporters or from reporters driven by Smad2/Smad4/FoxH1 complexes. We show that Arkadia specifically activates transcription via Smad3/Smad4 binding sites by inducing degradation of the transcriptional repressor SnoN. Arkadia is essential for TGF-beta-induced SnoN degradation, but it has little effect on SnoN levels in the absence of signal. Arkadia interacts with SnoN and induces its ubiquitination irrespective of TGF-beta/Activin signaling, but SnoN is efficiently degraded only when it forms a complex with both Arkadia and phosphorylated Smad2 or Smad3. Finally, we describe an esophageal cancer cell line (SEG-1) that we show has lost Arkadia expression and is deficient for SnoN degradation. Reintroduction of wild-type Arkadia restores TGF-beta-induced Smad3/Smad4-dependent transcription and SnoN degradation in these cells, raising the possibility that loss of Arkadia function may be relevant in cancer.

Publication Types:
PMID: 17591695 [PubMed - indexed for MEDLINE]

PMCID: PMC1952153