Related Experiment Video
Updated: May 20, 2026
06:54
Studying TGF-β Signaling and TGF-β-induced Epithelial-to-mesenchymal Transition in Breast Cancer and Normal Cells
Published on: October 27, 2020
USP11 augments TGFβ signalling by deubiquitylating ALK5
Mazin A Al-Salihi1, Lina Herhaus, Thomas Macartney
1Medical Research Council - Protein Phosphorylation Unit, College of Life Sciences, University of Dundee, Dow St., Dundee DD1 5EH, UK.
Open Biology
|July 10, 2012
Summary
The deubiquitylating enzyme USP11 enhances transforming growth factor beta (TGFβ) signaling by deubiquitylating the TGFβ receptor ALK5. USP11 overrides SMAD7 inhibition, promoting TGFβ-induced gene transcription and epithelial-mesenchymal transition.
Area of Science:
- Molecular Biology
- Cell Signaling
- Biochemistry
Background:
- Transforming growth factor beta (TGFβ) receptors signal via SMAD2/3 phosphorylation.
- SMAD7 negatively regulates TGFβ signaling by promoting receptor degradation.
- TGFβ signaling is crucial for embryogenesis and carcinogenesis, driving epithelial-mesenchymal transition.
Purpose of the Study:
- To identify novel regulators of the TGFβ pathway.
- To investigate the role of USP11 in TGFβ signaling.
- To elucidate the mechanism by which USP11 modulates TGFβ receptor activity.
Main Methods:
- Co-immunoprecipitation to identify USP11 as a SMAD7 interactor.
- Western blotting to assess SMAD2/3 phosphorylation.
- RNA interference (RNAi) to deplete USP11.
- Reporter assays to measure TGFβ-induced gene transcription.
- Analysis of epithelial-mesenchymal transition markers.
Main Results:
- USP11 interacts with SMAD7 and enhances TGFβ signaling.
- USP11 directly interacts with and deubiquitylates the TGFβ type I receptor, ALK5.
- USP11's deubiquitylase activity is essential for enhancing TGFβ-induced gene transcription.
- USP11 depletion inhibits TGFβ-induced SMAD2/3 phosphorylation and epithelial-mesenchymal transition.
- USP11 overrides the inhibitory effects of SMAD7 on TGFβ signaling.
Conclusions:
- USP11 is a positive regulator of TGFβ signaling.
- USP11 enhances TGFβ pathway activity by deubiquitylating ALK5, thereby promoting downstream signaling and epithelial-mesenchymal transition.
- USP11 represents a potential therapeutic target for modulating TGFβ-driven processes in development and disease.
Related Concept Videos
01:16TGF - β Signaling Pathway
The TGF-β signaling pathway regulates cell growth, differentiation, adhesion, motility, and development. TGF-β ligands that induce TGF-β signaling are synthesized in their latent form. Several proteases or cell surface receptors such as integrins act upon the latent form, releasing the active ligand. There are three types of mammalian TGF-βs: (TGF-β1, TGF-β2, and TGF-β3) that bind as homodimers or heterodimers to TGF-β receptors. The TGF-β receptors are of three kinds RI, RII, and RIII. The RI...
02:33Hedgehog Signaling Pathway
The Hedgehog gene (Hh) was first discovered due to its control of the growth of disorganized, hair-like bristles phenotype in Drosophila, much like hedgehog spines. Hh plays a crucial role in the development of organs and the maintenance of homeostasis in both invertebrates and vertebrates. However, while Drosophila has only one Hh protein, mammals have multiple functional Hedgehog proteins - Sonic (Shh), Desert (Dhh), and Indian Hedgehog (Ihh). All of these homologous proteins have adapted to...
01:15Receptor Downregulation in MVBs
Multivesicular bodies (MVBs) are mature endosomes that sort ubiquitinated proteins and then fuse with lysosomes to degrade the sorted proteins. Epidermal growth factor (EGF) and its receptor (EGFR) form a complex that can be internalized through endocytosis, sorted into an MVB, and later degraded.
The EGFR can initiate signaling pathways that lead to cell proliferation, migration, and differentiation. Overexpression of EGFR stimulates cells to proliferate. Excessive EGFR activation may...
The EGFR can initiate signaling pathways that lead to cell proliferation, migration, and differentiation. Overexpression of EGFR stimulates cells to proliferate. Excessive EGFR activation may...
02:04Covalently Linked Protein Regulators
Proteins can undergo many types of post-translational modifications, often in response to changes in their environment. These modifications play an important role in the function and stability of these proteins. Covalently linked molecules include functional groups, such as methyl, acetyl, and phosphate groups, and also small proteins, such as ubiquitin. There are around 200 different types of covalent regulators that have been identified.
These groups modify specific amino acids in a protein.
These groups modify specific amino acids in a protein.
01:12Role Of Notch Signalling In Intestinal Stem Cell Renewal
Notch signaling was first discovered in Drosophila melanogaster, where it is involved in cell lineage differentiation. Notch signaling regulates the maintenance and differentiation of intestinal stem cells or ISCs by controlling the expression of atonal homolog 1 or Atoh1. Atoh1 directs cells to differentiate into secretory cells.
Direct cell-to-cell contact is needed for the activation of Notch signaling. The signal is initiated when a notch ligand binds to a receptor on an adjacent cell, also...
Direct cell-to-cell contact is needed for the activation of Notch signaling. The signal is initiated when a notch ligand binds to a receptor on an adjacent cell, also...
01:24Regulation of Angiogenesis and Blood Supply
Rapidly dividing tumors, embryos, and wounded tissues require more oxygen than usual, lowering the oxygen concentration in the blood. At low oxygen or hypoxic conditions, an oxygen-sensitive transcription factor called the hypoxia-inducible factor 1 or HIF1 is activated. HIF1 is a dimeric protein of alpha (ɑ) and beta (β) subunits. Under optimal oxygen conditions, HIF1β is present in the nucleus while HIF1ɑ remains in the cytosol. HIF1ɑ is hydroxylated by prolyl hydroxylase and factor...