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Regulation of the transforming growth factor β pathway by reversible ubiquitylation.

Al-Salihi MA, Herhaus L, Sapkota GP - Open Biol (2012)

Bottom Line: The corruption of these regulatory processes results in aberrant TGFβ signalling and leads to numerous human diseases, including cancer.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.

View Article: PubMed Central - PubMed

Affiliation: Medical Research Council-Protein Phosphorylation Unit, Sir James Black Centre, University of Dundee, Dow Street, Dundee DD1 5EH, UK.

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.

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Related in: MedlinePlus

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.
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RSOB120082F1: 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.

Mentions: TGFβ signalling is initiated when ligands bind to their cognate receptors (figure 1). There are at least 42 different TGFβ ligands, which are divided into two main subgroups: the TGFβ family and the bone morphogenetic protein (BMP) family. Ligand binding induces specific quaternary complex formation of the transmembrane serine threonine kinase receptors. These receptors are divided into type I (ALK1-7) and type II (ACVR-IIA, ACVR-IIB, BMPR-II, AMHR-II and TGFβR-II). SMAD proteins are the intracellular transducers of the pathway; they are divided into specific subgroups: receptor-regulated (R-SMADs; 1–3, 5 and 8), the co-SMAD (4) and the inhibitory (I-) SMADs (6 and 7). Upon ligand binding, the type II receptors phosphorylate and activate the type I receptors. Activated type I receptors phosphorylate the R-SMADs at their C-terminal SXS motif. This induces R-SMAD complex formation with SMAD4 and nuclear translocation, where along with their nuclear cofactors they bind DNA and regulate transcription. The vast number of ligands and receptors allows for the formation of unique ligand–receptor complexes in distinct biological settings. In general, the TGFβ receptor subfamily signals through SMADs 2 and 3, while the BMP subfamily signals through SMADs 1, 5 and 8, although some crosstalk between the two pathways has been reported. A negative feedback loop is created by TGFβ- or BMP-induced transcription of the I-SMADs. I-SMADs inhibit the pathway by competing with R-SMADs for association with the type I receptors, or by recruiting E3 ubiquitin ligases and targeting the receptors for degradation. In the nucleus, a variety of nuclear cofactors are required for the R-SMADs to bind DNA and induce gene transcription (figure 1). Additionally, various histone and DNA modifiers are required for opening or closing sections of DNA to transcriptional regulation by R-SMADs [1,13–18]. While we focus on the role of reversible ubiquitylation in regulating the core components of the TGFβ pathway in this review, they can be further regulated by multiple post-translational modifications, which also impact the outcome of TGFβ signalling. Often it is the integration of all the regulatory inputs that determines the cellular responses to TGFβ signals.Figure 1.


Regulation of the transforming growth factor β pathway by reversible ubiquitylation.

Al-Salihi MA, Herhaus L, Sapkota GP - Open Biol (2012)

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.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3376735&req=5

RSOB120082F1: 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.
Mentions: TGFβ signalling is initiated when ligands bind to their cognate receptors (figure 1). There are at least 42 different TGFβ ligands, which are divided into two main subgroups: the TGFβ family and the bone morphogenetic protein (BMP) family. Ligand binding induces specific quaternary complex formation of the transmembrane serine threonine kinase receptors. These receptors are divided into type I (ALK1-7) and type II (ACVR-IIA, ACVR-IIB, BMPR-II, AMHR-II and TGFβR-II). SMAD proteins are the intracellular transducers of the pathway; they are divided into specific subgroups: receptor-regulated (R-SMADs; 1–3, 5 and 8), the co-SMAD (4) and the inhibitory (I-) SMADs (6 and 7). Upon ligand binding, the type II receptors phosphorylate and activate the type I receptors. Activated type I receptors phosphorylate the R-SMADs at their C-terminal SXS motif. This induces R-SMAD complex formation with SMAD4 and nuclear translocation, where along with their nuclear cofactors they bind DNA and regulate transcription. The vast number of ligands and receptors allows for the formation of unique ligand–receptor complexes in distinct biological settings. In general, the TGFβ receptor subfamily signals through SMADs 2 and 3, while the BMP subfamily signals through SMADs 1, 5 and 8, although some crosstalk between the two pathways has been reported. A negative feedback loop is created by TGFβ- or BMP-induced transcription of the I-SMADs. I-SMADs inhibit the pathway by competing with R-SMADs for association with the type I receptors, or by recruiting E3 ubiquitin ligases and targeting the receptors for degradation. In the nucleus, a variety of nuclear cofactors are required for the R-SMADs to bind DNA and induce gene transcription (figure 1). Additionally, various histone and DNA modifiers are required for opening or closing sections of DNA to transcriptional regulation by R-SMADs [1,13–18]. While we focus on the role of reversible ubiquitylation in regulating the core components of the TGFβ pathway in this review, they can be further regulated by multiple post-translational modifications, which also impact the outcome of TGFβ signalling. Often it is the integration of all the regulatory inputs that determines the cellular responses to TGFβ signals.Figure 1.

Bottom Line: The corruption of these regulatory processes results in aberrant TGFβ signalling and leads to numerous human diseases, including cancer.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.

View Article: PubMed Central - PubMed

Affiliation: Medical Research Council-Protein Phosphorylation Unit, Sir James Black Centre, University of Dundee, Dow Street, Dundee DD1 5EH, UK.

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.

Show MeSH
Related in: MedlinePlus