ArticleJournal of molecular medicine (Berlin, Germany)2017
TIMAP repression by TGFβ and HDAC3-associated Smad signaling regulates macrophage M2 phenotypic phagocytosis.
Article in Journal of molecular medicine (Berlin, Germany), 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 34 citations in OpenAlex.
- Microglial histone deacetylase-3 conditional deletion attenuates neurological deficits after intracerebral hemorrhage.Frontiers in cellular neuroscience · 2026Article
- Role of nuclear receptors, lipid metabolism, and mitochondrial function in the pathogenesis of diabetic kidney disease.American journal of physiology. Renal physiology · 2025Review
- Histone deacetylases and their inhibitors in kidney diseases.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Review
- HIF-1α Promotes Inflammatory Responses in Aspergillus Fumigatus Keratitis by Activating Pyroptosis Through Caspase-8/GSDMD Pathway.Investigative ophthalmology & visual science · 2025Article
- Epigenetic Regulation of EMP/EMT-Dependent Fibrosis.International journal of molecular sciences · 2024Review
- The involvement of HDAC3 in the pathogenesis of lung injury and pulmonary fibrosis.Frontiers in immunology · 2024Review
- The Role of TGF-β during Pregnancy and Pregnancy Complications.International journal of molecular sciences · 2023Review
- WDR74 facilitates TGF-β/Smad pathway activation to promote M2 macrophage polarization and diabetic foot ulcer wound healing in mice.Cell biology and toxicology · 2023Article
- Epigenetic modification in diabetic kidney disease.Frontiers in endocrinology · 2023Review
- A positive feedback loop: RAD18-YAP-TGF-β between triple-negative breast cancer and macrophages regulates cancer stemness and progression.Cell death discovery · 2022Article
- Histone deacetylase 3 (HDAC3) as an important epigenetic regulator of kidney diseases.Journal of molecular medicine (Berlin, Germany) · 2022Review
- Molecular mechanisms of histone deacetylases and inhibitors in renal fibrosis progression.Frontiers in molecular biosciences · 2022Review
- TIMAP Upregulation Correlates Negatively with Survival in HER2- Negative Subtypes of Breast Cancer.Asian Pacific journal of cancer prevention : APJCP · 2021Article
- Histone deacetylase 3 aberration inhibits Klotho transcription and promotes renal fibrosis.Cell death and differentiation · 2021Article
- EB virus-induced ATR activation accelerates nasopharyngeal carcinoma growth via M2-type macrophages polarization.Cell death & disease · 2020Article
- Indoleamine 2,3-Dioxygenase Regulates Macrophage Recruitment, Polarization and Phagocytosis in Aspergillus Fumigatus Keratitis.Investigative ophthalmology & visual science · 2020Article
- TIMAP inhibits endothelial myosin light chain phosphatase by competing with MYPT1 for the catalytic protein phosphatase 1 subunit PP1cβ.The Journal of biological chemistry · 2019Article
- Klotho recovery by genistein via promoter histone acetylation and DNA demethylation mitigates renal fibrosis in mice.Journal of molecular medicine (Berlin, Germany) · 2019Article
- Bladder Cancer Exhibiting High Immune Infiltration Shows the Lowest Response Rate to Immune Checkpoint Inhibitors.Frontiers in oncology · 2019Article
- Klotho preservation by Rhein promotes toll-like receptor 4 proteolysis and attenuates lipopolysaccharide-induced acute kidney injury.Journal of molecular medicine (Berlin, Germany) · 2018Article
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
TIMAP (TGFβ-inhibited membrane-associated protein) is an endothelium-enriched TGFβ downstream protein and structurally belongs to the targeting subunit of myosin phosphatase; however, the mechanism of TGFβ repressing TIMAP and its functional relevance to TGFβ bioactivity remain largely unknown. Here, we report that TIMAP is reduced in TGFβ-elevated mouse fibrotic kidney and highly expressed in macrophages. TGFβ repression of TIMAP is associated with HDAC3 upregulation and its recruitment by Smad2/3 at the Smad binding element on TIMAP promoter, whereas specific HDAC3 inhibition reversed the TIMAP repression, suggesting that TGFβ transcriptionally downregulates TIMAP through HDAC3-associated Smad signaling. Further investigation showed that TIMAP over-expression interrupted TGFβ-associated Smad signaling and TIMAP repression by TGFβ correlated with TGFβ-induced macrophage M2 polarization markers, migration, and phagocytosis-the processes promoted by phosphorylation of the putative TIMAP substrate myosin light chain (MLC). Consistently, TIMAP dephosphorylated MLC in macrophages and TGFβ induced macrophage migration and phagocytosis in TIMAP- and MLC phosphorylation-dependent manners, suggesting that TIMAP dephosphorylation of MLC constitutes an essential regulatory loop mitigating TGFβ-associated macrophage M2 phenotypic activities. Given that hyperactive TGFβ often causes excessive macrophage phagocytic activities potentially leading to various chronic disorders, the strategies targeting HDAC3/TIMAP axis might improve TGFβ-associated pathological processes. KEY MESSAGE: TIMAP is enriched in the endothelium and highly expressed in macrophages. TIMAP is suppressed by TGFβ via HDAC3-associated Smad signaling. TIMAP inhibits TGFβ signaling and TGFβ-associated macrophage M2 polarization. TIMAP dephosphorylation of MLC counteracts TGFβ-induced macrophage phagocytosis.
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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.