Translocation of TRPV4-PI3K{gamma} complexes to the plasma membrane drives myofibroblast transdifferentiation

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 (PI3K), forming nanomolar-affinity, intracellular TRPV4-PI3K complexes. TGF-β induced the recruitment of TRPV4-PI3K complexes to the plasma membrane and increased the activities of both TRPV4 and PI3K. Using gain- and loss-of-function approaches, we showed that both TRPV4 and PI3K 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 PI3K catalytic subunit (p110) in cells lacking PI3K revealed that only the noncatalytic, amino-terminal domain of p110 was necessary and sufficient for TGF-β–induced TRPV4 plasma membrane recruitment and myofibroblast transdifferentiation. These data suggest that TGF-β stimulates a noncanonica...
Source: Signal Transduction Knowledge Environment - Category: Science Authors: Tags: STKE Research Articles Source Type: news

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This study aimed to perform a time ‐lapse analysis of tumor response in patients with STS treated with trabectedin from 2 phase II clinical trials.We examined 66 patients with translocation ‐related sarcoma registered in 2 Japanese phase II clinical trials. All patients previously received standard therapy before the administration of trabectedin at 1.2 mg/m2 every 3  weeks. Imaging evaluation was performed according to the study protocol. The sum of the maximum diameters of the target lesions was calculated and analyzed over time.Among the 66 patients, 9 (13.6%) showed partial response (PR) to trabectedin. H...
Source: Cancer Medicine - Category: Cancer & Oncology Authors: Tags: ORIGINAL RESEARCH Source Type: research
ConclusionOur work demonstrates that Slit2 inhibits inflammatory responses and maintains myofilament contractile properties, thus contributing, at least in part, to the prevention of structural and functional damage during IR.
Source: Frontiers in Physiology - Category: Physiology Source Type: research
Systemic scleroderma (SSc) is an autoimmune disease that affects over 2.5 million people globally. SSc results in dysfunctional connective tissues with excessive profibrotic signaling, affecting skin, cardiovascular, and particularly lung tissue. Over three-quarters of individuals with SSc develop pulmonary fibrosis within 5 years, the main cause of SSc mortality. No approved medicines to manage lung SSc currently exist. Recent research suggests that profibrotic signaling by transforming growth factor β (TGF-β) is directly tied to SSc. Previous studies have also shown that ubiquitin E3 ligases potently control TG...
Source: Journal of Biological Chemistry - Category: Chemistry Authors: Tags: Protein Synthesis and Degradation Source Type: research
In up to 15% of acute myeloid leukemias (AMLs), a recurring chromosomal translocation, termed t(8;21), generates the AML1–eight–twenty-one (ETO) leukemia fusion protein, which contains the DNA-binding domain of Runt-related transcription factor 1 (RUNX1) and almost all of ETO. RUNX1 and the AML1–ETO fusion protein are coexpressed in t(8;21) AML cells and antagonize each other's gene-regulatory functions. AML1–ETO represses transcription of RUNX1 target genes by competitively displacing RUNX1 and recruiting corepressors such as histone deacetylase 3 (HDAC3). Recent studies have shown that AML1–...
Source: Journal of Biological Chemistry - Category: Chemistry Authors: Tags: Gene Regulation Source Type: research
In conclusion, berberine-induced nuclear translocation of FXR and LXRα could activate OATP1B1 promoter, resulting in enhanced expression of OATP1B1 and increased uptake of rosuvastatin.
Source: Frontiers in Pharmacology - Category: Drugs & Pharmacology Source Type: research
Mammalian mitochondrial permeability transition pore (MPTP), across the inner and outer membranes of mitochondria, is a nonspecific channel for signal transduction or material transfer between mitochondrial matrix and cytoplasm such as maintenance of Ca2+ homeostasis, regulation of oxidative stress signals, and protein translocation evoked by some of stimuli. Continuous MPTP opening has been proved to stimulate neuronal apoptosis in ischemic stroke. Meanwhile, inhibition of MPTP overopening-induced apoptosis has shown excellent efficacy in the treatment of ischemic stroke. Among of which, the potential molecular mechanisms...
Source: Frontiers in Pharmacology - Category: Drugs & Pharmacology Source Type: research
Abstract Long noncoding RNAs (lncRNAs) play critical roles in tumour progression and metastasis. Emerging evidence indicates that the lncRNA X inactive-specific transcript (XIST) is dysregulated in several tumor types, including non-small cell lung cancer (NSCLC). However, in NSCLC and other cancers the oncogenic mechanism of XIST remains incompletely understood. Here, we confirmed that XIST is upregulated in human NSCLC specimens, and is especially overexpressed in tumors previously treated with cisplatin (cis-diamminedichloroplatinum(II); DDP). In vitro, XIST knockdown inhibited NSCLC cell growth and promoted DD...
Source: Aging - Category: Biomedical Science Authors: Tags: Aging (Albany NY) Source Type: research
Abstract In the present study,to investigate contributions of complement 3 (C3)to development of the pathogenesis of hypertension, we evaluated theformationof renin-producing cells and roles of C3 in renin generation during differentiationof primarybone marrow-mesenchymal stem cells (MSCs) from C57BL/6 mice, Wistar-Kyoto(WKY) rats and spontaneously hypertensive rats (SHRs)to smooth muscle cells (SMCs)with transforming growth factor-β1.The expression of renin transiently increased with increases in transcription factor liver X receptor a(LXRa), and expression of C3 and Krüppel-like factor5 (KLF5)increased...
Source: American Journal of Physiology. Cell Physiology - Category: Cytology Authors: Tags: Am J Physiol Cell Physiol Source Type: research
by Susan Nadin-Davis, Tore Buchanan, Larissa Nituch, Christine Fehlner-Gardiner Despite proactive measures to prevent raccoon rabies entering Canada from the United States, several incursions of this disease have occurred. The largest outbreak, first reported in December 2015 in the city of Hamilton, Ontario, has resulted in the reporting of 449 animal cases as of December 31 , 2018. Initial phylogenetic studies on the index case suggested that this outbreak was not due to local cross-border spread from the Niagara region of the United States where raccoon rabies has persisted for several years. Phylogenetic analysis of w...
Source: PLoS Neglected Tropical Diseases - Category: Tropical Medicine Authors: Source Type: research
Discussion and conclusions: These results suggested that CNE is a promising agent for functional food and hepatoprotective drug against ALI. PMID: 32202453 [PubMed - as supplied by publisher]
Source: Pharmaceutical Biology - Category: Drugs & Pharmacology Tags: Pharm Biol Source Type: research
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