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Mol. Cell. Biol. doi:10.1128/MCB.00664-07
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Arkadia activates Smad3/Smad4-dependent transcription by triggering signal-induced SnoN degradation

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; Mammalian Neurogenesis, MRC Clinical Sciences Centre, Imperial School of Medicine, Hammersmith Hospital, London W12 0NN, UK

^* To whom correspondence should be addressed. Email: caroline.hill{at}cancer.org.uk.

	Abstract

E3 ubiquitin ligases play important roles in regulating TGF-/Smad signaling. Screening of an E3 ubiquitin ligase siRNA library, using TGF- 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- 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--induced SnoN degradation, but has little effect on SnoN levels in the absence of signal. Arkadia interacts with SnoN and induces its ubiquitination irrespective of TGF-/Activin signaling, but SnoN is only efficiently degraded 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--induced Smad3/Smad4-dependent transcription and SnoN degradation in these cells, raising the possibility that loss of Arkadia function may be relevant in cancer.

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