Regulation of the transforming growth factor β pathway by reversible ubiquitylation

Abstract

The transforming growth factor β (TGFβ) signalling pathway plays a central role during embryonic development and in adult tissue homeostasis. It regulates gene transcription through a signalling cascade from cell surface receptors to intracellular SMAD transcription factors and their nuclear cofactors. The extent, duration and potency of signalling in response to TGFβ cytokines are intricately regulated by complex biochemical processes. The corruption of these regulatory processes results in aberrant TGFβ signalling and leads to numerous human diseases, including cancer. Reversible ubiquitylation of pathway components is a key regulatory process that plays a critical role in ensuring a balanced response to TGFβ signals. Many studies have investigated the mechanisms by which various E3 ubiquitin ligases regulate the turnover and activity of TGFβ pathway components by ubiquitylation. Moreover, recent studies have shed new light into their regulation by deubiquitylating enzymes. In this report, we provide an overview of current understanding of the regulation of TGFβ signalling by E3 ubiquitin ligases and deubiquitylases.

Keywords: DUBs; deubiquitylation; transforming growth factor; ubiquitin; ubiquitination; ubiquitylation.

Figure 1.

The logic of TGFβ signalling from the membrane to nucleus. Upon ligand binding, the TGFβ/BMP receptor kinases mediate the phosphorylation of R-SMADs. R-SMADs are depicted showing their MH1/Linker/MH2 domains. This induces the association of R-SMADs with SMAD4 and their nuclear translocation. In the nucleus, the SMADs form transcription complexes with multiple cofactors and regulate the transcription of multiple target genes. Most of the known transcriptional cofactors of SMADs are indicated, although not all are described in the text.

Figure 2.

Regulation of the TGFβ–BMP receptor complexes by reversible ubiquitylation. Sketch of how reversible ubiquitylation of the receptor complexes may regulate pathway signalling. Detailed description is covered in the text.

Figure 3.

Regulation of SMAD transcription factors and nuclear cofactors by reversible ubiquitylation. An overview of how reversible ubiquitylation of SMAD transcription factors and associated nuclear cofactors may impact the SMAD-dependent transcription. Most of the reported E3s and DUBs known to regulate specific proteins are included. The reported mechanisms by which different E3 ubiquitin ligases and DUBs regulate SMAD proteins and associated cofactors are described in the text.