E3 ubiquitin ligases play important roles in regulating transforming growth factor ␤ (TGF-␤)/Smad signaling. Screening of an E3 ubiquitin ligase small interfering RNA 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 it 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 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-␤-induced Smad3/Smad4-dependent transcription and SnoN degradation in these cells, raising the possibility that loss of Arkadia function may be relevant in cancer.The transforming growth factor ␤ (TGF-␤) superfamily of ligands comprises TGF-␤s, Activin/Nodal family members, bone morphogenetic proteins (BMPs), and growth and differentiation factors (26). These ligands signal through a heterotetrameric complex of two type II receptors and two type I receptors, both serine/threonine kinases. The ligand brings the receptors together, enabling the type II receptor to phosphorylate and activate the type I receptor. The activated type I receptor signals to the nucleus primarily through phosphorylation of receptor-regulated Smads (R-Smads) (12). Broadly speaking, TGF-␤ and Activin/Nodal ligands induce activation of the R-Smads, Smad2 and Smad3, while the BMP and growth and differentiation factor ligands induce activation of Smad1, -5, and -8. Activated R-Smads form homomeric complexes and heteromeric complexes with Smad4 which accumulate in the nucleus. There they are recruited to promoter elements in conjunction with other transcription factors to regulate transcription both positively and negatively.Different Smad complexes target different promoter elements. Smad3/Smad4 complexes bind directly to direct or inverted repeats of the GTCT sequence or its reverse complement, AGAC (44), such as those found in the PAI-1 promoter (6) or c-Jun promoter (41). A spliced variant of Smad2 (Smad2⌬exon3) also binds as a complex with Smad4 to these same repeated GTCT or AGAC sequences (5, 42). Complexes of Smad4 with Smad1 or Smad5 also bind DNA directly and have recently been shown to recognize a GRCKNCN 5 GTCT consensus in cooperation with the zinc finger protein Schnurri (...

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We study the determinants of average pay across all levels of staff seniority for UK banks between 2003 and 2012. We show that pay is affected by agency problems but not by bank operating performance. Average pay does not depend on accounting outcomes at the bank level. By contrast, average pay is positively affected by the presence of a Remuneration Committee and the proportion of Non-Executives on the Board. These findings indicate that bank pay is determined by agency issues, not bank accounting performance. Our results have practical implications for bank shareholders and regulators, suggesting the need for greater transparency in governance of bank pay.

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