ArticleScience signaling2019
Translocation of TRPV4-PI3Kγ complexes to the plasma membrane drives myofibroblast transdifferentiation.
Article in Science signaling, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers.
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Who cites it
36 citing papers in PubMed, 53 citations in OpenAlex.
- mExperimental and therapeutic medicine · 2026Review
- The cell with many faces: lung macrophage plasticity and function in response to environmental and pathogenic insults.Physiological reviews · 2026Review
- 25+ Years of TRPV4: From Discovery to Translational Horizons.Research square · 2026Article
- Integration of cAMP and TRPV4 Signaling to Optimize Collagen Remodeling for Management of Fibrosis.Cells · 2025Review
- The mechanosensitive channel TRPV4 inhibits pulmonary inflammation by limiting NF-κB signaling in alveolar macrophages.Science signaling · 2025Article
- Fibrosis: cross-organ biology and pathways to development of innovative drugs.Nature reviews. Drug discovery · 2025Review
- TRPV4 controls circadian and pathological ocular hypertension.The Journal of physiology · 2025Article
- TRPV4 activation by TGFβ2 enhances cellular contractility and drives ocular hypertension.eLife · 2025Article
- Insulin potentiates mechanical responses in small dorsal root ganglion neurons by increasing the sensitization of TRPV4 channels.American journal of physiology. Cell physiology · 2025Article
- Article
- Trpv4-mediated mechanotransduction regulates the differentiation of valvular interstitial cells to myofibroblasts: implications for aortic valve stenosis.American journal of physiology. Cell physiology · 2025Article
- Scaffold Proteins in Fibrotic Diseases of Visceral Organs.Biomolecules · 2025Review
- Imaging methods to monitor and quantify cell differentiation.Frontiers in cell and developmental biology · 2025Review
- A QUARTER CENTURY OF CALCIUM-PERMEABLE ION CHANNEL, TRPV4: PERSPECTIVES ON EXPRESSION AND FUNCTION IN ENDOTHELIAL CELLS-TIME TO TRANSLATE.Transactions of the American Clinical and Climatological Association · 2025Review
- Current Understanding of Pulmonary Fibrosis: Pathogenesis, Diagnosis, and Therapeutic Approaches.Canadian respiratory journal · 2025Review
- Acute contact with profibrotic macrophages mechanically activates fibroblasts via αvβ3 integrin-mediated engagement of Piezo1.Science advances · 2024Article
- Fibroblast and myofibroblast activation in normal tissue repair and fibrosis.Nature reviews. Molecular cell biology · 2024Review
- TRPV4 subserves physiological and pathological elevations in intraocular pressure.Research square · 2024Article
- LPS exacerbates TRPV4-mediated itch through the intracellular TLR4-PI3K signalling.Journal of cellular and molecular medicine · 2024Article
- Exploring the potential mechanism of WuFuYin against hypertrophic scar using network pharmacology and molecular docking.World journal of clinical cases · 2024Article
Corrections and comments
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Authors and funding
8 authors at 2 institutions in 1 country.
Funding
Abstract
Myofibroblasts are key contributors to pathological fibrotic conditions of several major organs. The transdifferentiation of fibroblasts into myofibroblasts requires both a mechanical signal and transforming growth factor-β (TGF-β) signaling. The cation channel transient receptor potential vanilloid 4 (TRPV4) is a critical mediator of myofibroblast transdifferentiation and in vivo fibrosis through its mechanosensitivity to extracellular matrix stiffness. Here, we showed that TRPV4 promoted the transdifferentiation of human and mouse lung fibroblasts through its interaction with phosphoinositide 3-kinase γ (PI3Kγ), forming nanomolar-affinity, intracellular TRPV4-PI3Kγ complexes. TGF-β induced the recruitment of TRPV4-PI3Kγ complexes to the plasma membrane and increased the activities of both TRPV4 and PI3Kγ. Using gain- and loss-of-function approaches, we showed that both TRPV4 and PI3Kγ were required for myofibroblast transdifferentiation as assessed by the increased production of α-smooth muscle actin and its incorporation into stress fibers, cytoskeletal changes, collagen-1 production, and contractile force. Expression of various mutant forms of the PI3Kγ catalytic subunit (p110γ) in cells lacking PI3Kγ revealed that only the noncatalytic, amino-terminal domain of p110γ was necessary and sufficient for TGF-β-induced TRPV4 plasma membrane recruitment and myofibroblast transdifferentiation. These data suggest that TGF-β stimulates a noncanonical scaffolding action of PI3Kγ, which recruits TRPV4-PI3Kγ complexes to the plasma membrane, thereby increasing myofibroblast transdifferentiation. Given that both TRPV4 and PI3Kγ have pleiotropic actions, targeting the interaction between them could provide a specific therapeutic approach for inhibiting myofibroblast transdifferentiation.
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Registered trials
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.