ArticleThe Journal of biological chemistry2013
The four and a half LIM-only protein 2 (FHL2) activates transforming growth factor β (TGF-β) signaling by regulating ubiquitination of the E3 ligase Arkadia.
Article in The Journal of biological chemistry, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 38 citations in OpenAlex.
- FHL2 production enabled new insight into its flexibility and unexpected binding stoichiometry with β-catenin.Journal of structural biology: X · 2026Article
- Therapeutic targeting of AREL1 in hepatic stellate cells attenuates MASH-related liver fibrosis.Nature communications · 2026Article
- The Ubiquitin Script: writing protein fates in chains.Essays in biochemistry · 2025Review
- The roles of FHL2 in cancer.Clinical and experimental medicine · 2023Review
- The UAS thioredoxin-like domain of UBXN7 regulates E3 ubiquitin ligase activity of RNF111/Arkadia.BMC biology · 2023Article
- E3 Ubiquitin Ligases: Key Regulators of TGFβ Signaling in Cancer Progression.International journal of molecular sciences · 2021Review
- Article
- PDLIM5 inhibits STUB1-mediated degradation of SMAD3 and promotes the migration and invasion of lung cancer cells.The Journal of biological chemistry · 2020Article
- LIM-only protein FHL2 attenuates vascular tissue factor activity, inhibits thrombus formation in mice andHaematologica · 2020Article
- Article
- The complex of TRIP-Br1 and XIAP ubiquitinates and degrades multiple adenylyl cyclase isoforms.eLife · 2017Article
- LIM-Only Protein FHL2 Is a Negative Regulator of Transforming Growth Factor β1 Expression.Molecular and cellular biology · 2017Article
- Molecular Analysis of a Short-term Model of β-Glucans-Trained Immunity Highlights the Accessory Contribution of GM-CSF in Priming Mouse Macrophages Response.Frontiers in immunology · 2017Article
- Four and a half LIM domains 2 contributes to the development of human tongue squamous cell carcinoma.Journal of molecular histology · 2016Article
- Multiple Arkadia/RNF111 structures coordinate its Polycomb body association and transcriptional control.Molecular and cellular biology · 2014Article
- Transcriptional regulation of the tumor suppressor FHL2 by p53 in human kidney and liver cells.PloS one · 2014Article
- LIM-only protein FHL2 activates NF-κB signaling in the control of liver regeneration and hepatocarcinogenesis.Molecular and cellular biology · 2013Article
- Epithelial expression of FHL2 is negatively associated with metastasis-free and overall survival in colorectal cancer.British journal of cancer · 2013Article
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Authors and funding
9 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Arkadia is a RING-based ubiquitin ligase that positively regulates TGF-β signaling by targeting several pathway components for ubiquitination and degradation. However, little is known about the mechanisms controlling Arkadia activity. Here we show that the LIM-only protein FHL2 binds and synergistically cooperates with Arkadia to activate Smad3/Smad4-dependent transcription. Knockdown of FHL2 by RNA interference decreases Arkadia level and restricts the amplitude of Arkadia-induced TGF-β target gene responses. We found that Arkadia is ubiquitinated via K63- and K27-linked polyubiquitination. A single mutation at the RING domain that abolishes the E3 activity diminishes Arkadia ubiquitination, indicating that this modification partly involves autocatalytic process. Mutation of seven lysines at the C-terminal region of Arkadia severely impairs ubiquitination through the K27 but not the K63 linkage and slows down the turnover of Arkadia, suggesting that K27-linked polyubiquitination might promote proteolysis-dependent regulation of Arkadia. We show that FHL2 increases the half-life of Arkadia through inhibition of ubiquitin chain assembly on the protein, which provides a molecular basis for functional cooperation between Arkadia and FHL2 in enhancing TGF-β signaling. Our study uncovers a novel regulatory mechanism of Arkadia by ubiquitination and identifies FHL2 as important regulator of Arkadia ubiquitination and TGF-β signal transduction.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.