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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

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.
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RSOB120082F2: 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.

Mentions: Receptor complex assembly and activation upon binding TGFβ ligands are central to the activation of intracellular signalling. The activity and integrity of type II and type I TGFβ receptors can be modulated by several strategies: dephosphorylation of the activated receptors, interfering with the receptor/R-SMAD binding, changing receptor localization and/or targeting receptors for proteasomal degradation. I-SMADs play a crucial role in some of these strategies by modulating the activity and stability of active TGFβ receptor complexes. SMAD7 was reported to inhibit the TGFβ pathway by not only interfering with R-SMAD phosphorylation but also recruiting the E3 ubiquitin ligases SMURF1 and SMURF2 to the receptor complex (figure 2) [35,36]. This led to both receptors (ALK5 and TGFβR-II) and SMAD7 being ubiquitylated and targeted for degradation. Similarly, SMAD6/7 has been described to direct SMURF1 to ALK6 and mediates receptor ubiquitylation and degradation [37]. Both I-SMADs and SMURF1/2 are transcriptional targets of TGFβ and BMP signals, thereby creating a negative feedback loop [38,39]. A glycosyl phosphatidylinositol-anchored protein, CD109, further enhances the SMAD7–SMURF2 receptor complex interaction, strengthening the negative feedback [40,41]. Conversely, a recent study demonstrated that a protein named TGF-β-stimulated clone 22 (TSC-22), which is induced by TGFβ, inhibits the SMAD7–SMURF complex from binding, ubiquitylating and degrading the receptor complex. As expected, this leads to enhanced TGFβ signalling that translated physiologically into increased TGFβ-induced cellular differentiation [42]. Tribbles homologue 3 (TRB3) is another TGFβ-induced gene capable of enhancing pathway signalling in a positive feedback loop. TRB3 enhances SMAD3 nuclear localization and induces degradation of SMURF2 promoting cell migration, invasion and epithelial to mesenchymal transition (EMT) [43]. In human renal cell carcinomas, enhanced SMURF2 expression causes the reduction in levels of type II TGFβ receptor by proteasomal degradation [8]. SMURF1 and SMURF2 belong to the NEDD4-like family of HECT E3 ubiquitin ligases and are characterized by the presence of a conserved C2-WW-HECT domain structure [44]. While the C2 domain regulates the subcellular localization, the WW domains are 38–40 residue motifs characterized by two highly conserved tryptophans and folded as a three-strand β sheet that associate with the proline-rich ‘PPXY’ motif (also known as ‘PY’ motif) [45]. The PY motif present in the linker region of SMAD7 interacts with one of the WW domains of SMURF1/2 [35]. Other members of the NEDD4-like family, WWP1 and NEDD4L, have also been shown to interact with SMAD7 and target ALK5 for ubiquitylation and degradation. However, unlike SMURF1/2, they did not target SMAD7 itself for ubiquitin-mediated degradation, possibly providing a stronger and longer lasting negative regulation of the pathway [46–48]. In our studies, we have identified three further members of the NEDD4-like family of E3s, namely NEDD4, WWP2 and ITCH, as SMAD6/7 interactors. These are also likely to act in a similar mode to regulate the activity and stability of the TGFβ receptors. The precise nature of ubiquitin attachment and the sites for ubiquitylation on TGFβ receptors remain undefined. While several E3s have been implicated to act on the TGFβ receptors, to date very few E2-ubiquitin-conjugating enzymes have been assigned. SMAD7 has been reported to facilitate the recruitment of UbcH7, an E2 enzyme, to SMURF2 thereby providing a pathway-specific control on SMURF2 activity [49].Figure 2.


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

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

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

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

RSOB120082F2: 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.
Mentions: Receptor complex assembly and activation upon binding TGFβ ligands are central to the activation of intracellular signalling. The activity and integrity of type II and type I TGFβ receptors can be modulated by several strategies: dephosphorylation of the activated receptors, interfering with the receptor/R-SMAD binding, changing receptor localization and/or targeting receptors for proteasomal degradation. I-SMADs play a crucial role in some of these strategies by modulating the activity and stability of active TGFβ receptor complexes. SMAD7 was reported to inhibit the TGFβ pathway by not only interfering with R-SMAD phosphorylation but also recruiting the E3 ubiquitin ligases SMURF1 and SMURF2 to the receptor complex (figure 2) [35,36]. This led to both receptors (ALK5 and TGFβR-II) and SMAD7 being ubiquitylated and targeted for degradation. Similarly, SMAD6/7 has been described to direct SMURF1 to ALK6 and mediates receptor ubiquitylation and degradation [37]. Both I-SMADs and SMURF1/2 are transcriptional targets of TGFβ and BMP signals, thereby creating a negative feedback loop [38,39]. A glycosyl phosphatidylinositol-anchored protein, CD109, further enhances the SMAD7–SMURF2 receptor complex interaction, strengthening the negative feedback [40,41]. Conversely, a recent study demonstrated that a protein named TGF-β-stimulated clone 22 (TSC-22), which is induced by TGFβ, inhibits the SMAD7–SMURF complex from binding, ubiquitylating and degrading the receptor complex. As expected, this leads to enhanced TGFβ signalling that translated physiologically into increased TGFβ-induced cellular differentiation [42]. Tribbles homologue 3 (TRB3) is another TGFβ-induced gene capable of enhancing pathway signalling in a positive feedback loop. TRB3 enhances SMAD3 nuclear localization and induces degradation of SMURF2 promoting cell migration, invasion and epithelial to mesenchymal transition (EMT) [43]. In human renal cell carcinomas, enhanced SMURF2 expression causes the reduction in levels of type II TGFβ receptor by proteasomal degradation [8]. SMURF1 and SMURF2 belong to the NEDD4-like family of HECT E3 ubiquitin ligases and are characterized by the presence of a conserved C2-WW-HECT domain structure [44]. While the C2 domain regulates the subcellular localization, the WW domains are 38–40 residue motifs characterized by two highly conserved tryptophans and folded as a three-strand β sheet that associate with the proline-rich ‘PPXY’ motif (also known as ‘PY’ motif) [45]. The PY motif present in the linker region of SMAD7 interacts with one of the WW domains of SMURF1/2 [35]. Other members of the NEDD4-like family, WWP1 and NEDD4L, have also been shown to interact with SMAD7 and target ALK5 for ubiquitylation and degradation. However, unlike SMURF1/2, they did not target SMAD7 itself for ubiquitin-mediated degradation, possibly providing a stronger and longer lasting negative regulation of the pathway [46–48]. In our studies, we have identified three further members of the NEDD4-like family of E3s, namely NEDD4, WWP2 and ITCH, as SMAD6/7 interactors. These are also likely to act in a similar mode to regulate the activity and stability of the TGFβ receptors. The precise nature of ubiquitin attachment and the sites for ubiquitylation on TGFβ receptors remain undefined. While several E3s have been implicated to act on the TGFβ receptors, to date very few E2-ubiquitin-conjugating enzymes have been assigned. SMAD7 has been reported to facilitate the recruitment of UbcH7, an E2 enzyme, to SMURF2 thereby providing a pathway-specific control on SMURF2 activity [49].Figure 2.

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