Abstract:
:Idiopathic pulmonary fibrosis (IPF) is an incurable disease of the lung that is characterized by excessive deposition of extracellular matrix (ECM), resulting in disruption of normal lung function. The signals regulating fibrosis include both transforming growth factor beta (TGF-β) and tissue rigidity and a major signaling pathway implicated in fibrosis involves activation of the GTPase RhoA. During studies exploring how elevated RhoA activity is sustained in IPF, we discovered that not only is RhoA activated by profibrotic stimuli but also that the expression of Rnd3, a major antagonist of RhoA activity, and the activity of p190RhoGAP (p190), a Rnd3 effector, are both suppressed in IPF fibroblasts. Restoration of Rnd3 levels in IPF fibroblasts results in an increase in p190 activity, a decrease in RhoA activity and a decrease in the overall fibrotic phenotype. We also find that treatment with IPF drugs nintedanib and pirfenidone decreases the fibrotic phenotype and RhoA activity through up-regulation of Rnd3 expression and p190 activity. These data provide evidence for a pathway in IPF where fibroblasts down-regulate Rnd3 levels and p190 activity to enhance RhoA activity and drive the fibrotic phenotype.
journal_name
Mol Biol Celljournal_title
Molecular biology of the cellauthors
Monaghan-Benson E,Wittchen ES,Doerschuk CM,Burridge Kdoi
10.1091/mbc.E17-11-0642subject
Has Abstractpub_date
2018-09-01 00:00:00pages
2165-2175issue
18eissn
1059-1524issn
1939-4586journal_volume
29pub_type
杂志文章abstract::The small GTPase Ran is essential for spindle assembly. Ran is proposed to act through its nuclear import receptors importin alpha and/or importin beta to control the sequestration of proteins necessary for spindle assembly. To date, the molecular mechanisms by which the Ran pathway functions remain unclear. Using pur...
journal_title:Molecular biology of the cell
pub_type: 杂志文章
doi:10.1091/mbc.e03-07-0454
更新日期:2004-01-01 00:00:00
abstract::The membrane-trafficking pathway mediated by tetanus neurotoxin-insensitive vesicle-associated membrane protein (TI-VAMP) in neurons is still unknown. We show herein that TI-VAMP expression is necessary for neurite outgrowth in PC12 cells and hippocampal neurons in culture. TI-VAMP interacts with plasma membrane and e...
journal_title:Molecular biology of the cell
pub_type: 杂志文章
doi:10.1091/mbc.e03-03-0147
更新日期:2003-10-01 00:00:00
abstract::Macrophage polarization contributes to a number of human pathologies. This is exemplified for tumor-associated macrophages (TAMs), which display a polarized M2 phenotype, closely associated with promotion of angiogenesis and suppression of innate immune responses. We present evidence that induction of apoptosis in tum...
journal_title:Molecular biology of the cell
pub_type: 杂志文章
doi:10.1091/mbc.e06-12-1096
更新日期:2007-10-01 00:00:00
abstract::Vascular endothelial cells are important in a variety of physiological and pathophysiological processes. The growth and functions of vascular endothelial cells are regulated both by soluble mitogenic and differentiation factors and by interactions with the extracellular matrix; however, relatively little is known abou...
journal_title:Molecular biology of the cell
pub_type: 杂志文章
doi:10.1091/mbc.9.8.1969
更新日期:1998-08-01 00:00:00
abstract::The concept of critical concentration (CC) is central to understanding the behavior of microtubules (MTs) and other cytoskeletal polymers. Traditionally, these polymers are understood to have one CC, measured in multiple ways and assumed to be the subunit concentration necessary for polymer assembly. However, this fra...
journal_title:Molecular biology of the cell
pub_type: 杂志文章
doi:10.1091/mbc.E19-02-0101
更新日期:2020-03-19 00:00:00
abstract::The kinetochore is a crucial structure for faithful chromosome segregation during mitosis and is formed in the centromeric region of each chromosome. The 16-subunit protein complex known as the constitutive centromere-associated network (CCAN) forms the foundation for kinetochore assembly on the centromeric chromatin....
journal_title:Molecular biology of the cell
pub_type: 杂志文章
doi:10.1091/mbc.E15-07-0531
更新日期:2015-11-01 00:00:00
abstract::During the cell cycle, Cdc2-cyclin B kinase abruptly becomes active and triggers the entry into mitosis/meiosis. Recently, it was found that inactive Cdc2-cyclin B is present in aggregates in immature starfish oocytes and becomes disaggregated at the time of its activation during maturation. We discuss a possible scen...
journal_title:Molecular biology of the cell
pub_type: 杂志文章
doi:10.1091/mbc.e03-04-0248
更新日期:2003-11-01 00:00:00
abstract::In mammals, a finite population of oocytes is generated during embryogenesis, and proper oocyte meiotic divisions are crucial for fertility. Sperm-associated antigen 1 (SPAG-1) has been implicated in infertility and tumorigenesis; however, its relevance in cell cycle programs remains rudimentary. Here we explore a nov...
journal_title:Molecular biology of the cell
pub_type: 杂志文章
doi:10.1091/mbc.E16-02-0132
更新日期:2016-06-01 00:00:00
abstract::More than 130 different mutations in the gap junction integral plasma membrane protein connexin32 (Cx32) have been linked to the human peripheral neuropathy X-linked Charcot-Marie-Tooth disease (CMTX). How these various mutants are processed by the cell and the mechanism(s) by which they cause CMTX are unknown. To add...
journal_title:Molecular biology of the cell
pub_type: 杂志文章
doi:10.1091/mbc.11.6.1933
更新日期:2000-06-01 00:00:00
abstract::Of the uncloned ODA genes required for outer dynein arm assembly in Chlamydomonas, ODA5 and ODA10 are of particular interest because they do not encode known subunits of the outer arm or the outer dynein arm-docking complex (ODA-DC), and because genetic studies suggest their products interact. Beginning with a tagged ...
journal_title:Molecular biology of the cell
pub_type: 杂志文章
doi:10.1091/mbc.e03-11-0820
更新日期:2004-06-01 00:00:00
abstract::Dog thyroid epithelial cells in primary culture constitute a physiologically relevant model of positive control of DNA synthesis initiation and G0-S prereplicative phase progression by cAMP as a second messenger for thyrotropin (thyroid-stimulating hormone [TSH]). As previously shown in this system, the cAMP-dependent...
journal_title:Molecular biology of the cell
pub_type: 杂志文章
doi:10.1091/mbc.11.3.1061
更新日期:2000-03-01 00:00:00
abstract::Specificity of vesicular transport is determined by pair-wise interaction between receptors (SNAP receptors or SNAREs) associated with a transport vesicle and its target membrane. Two additional factors, N-ethylmaleimide-sensitive fusion protein (NSF) and soluble NSF attachment protein (SNAP) are ubiquitous components...
journal_title:Molecular biology of the cell
pub_type: 杂志文章
doi:10.1091/mbc.9.7.1633
更新日期:1998-07-01 00:00:00
abstract::Jak tyrosine kinases have a unique domain structure containing a kinase domain (JH1) adjacent to a catalytically inactive pseudokinase domain (JH2). JH2 is crucial for inhibition of basal Jak activity, but the mechanism of this regulation has remained elusive. We show that JH2 negatively regulated Jak2 in bacterial ce...
journal_title:Molecular biology of the cell
pub_type: 杂志文章
doi:10.1091/mbc.e02-06-0342
更新日期:2003-04-01 00:00:00
abstract::The gene encoding NFKB1 is autoregulated, responding to NF-kappa B/Rel activation through NF-kappa B binding sites in its promoter, which also contains putative sites for Ets proteins. One of the Ets sites, which we refer to as EBS4, is located next to an NF-kappa B/Rel binding site, kB3, which is absolutely required ...
journal_title:Molecular biology of the cell
pub_type: 杂志文章
doi:10.1091/mbc.8.2.313
更新日期:1997-02-01 00:00:00
abstract::The juvenile form of neuronal ceroid lipofuscinoses (JNCLs), or Batten disease, results from mutations in the CLN3 gene, and it is characterized by the accumulation of lipopigments in the lysosomes of several cell types and by extensive neuronal death. We report that the yeast model for JNCL (btn1-Delta) that lacks BT...
journal_title:Molecular biology of the cell
pub_type: 杂志文章
doi:10.1091/mbc.e06-11-1053
更新日期:2007-07-01 00:00:00
abstract::Intracellular free calcium ([Ca2+]i) has been proposed to play an important part in the regulation of the cell cycle. Although a number of studies have shown that stimulation of quiescent cells with growth factors causes an immediate rise in [Ca2+]i (Rabinovitch et al., 1986; Vincentini and Villereal, 1986; Hesketh et...
journal_title:Molecular biology of the cell
pub_type: 杂志文章
doi:10.1091/mbc.4.3.293
更新日期:1993-03-01 00:00:00
abstract::Precise chromosome transmission in cell division cycle is maintained by a number of genes. The attempt made in the present study was to isolate temperature-sensitive (ts) fission yeast mutants that display high loss rates of minichromosomes at permissive or semipermissive temperature (designated mis). By colony color ...
journal_title:Molecular biology of the cell
pub_type: 杂志文章
doi:10.1091/mbc.5.10.1145
更新日期:1994-10-01 00:00:00
abstract::In kinetochores, the Ndc80 complex couples the energy in a depolymerizing microtubule to perform the work of moving chromosomes. The complex directly binds microtubules using an unstructured, positively charged N-terminal tail located on Hec1/Ndc80. Hec1/Ndc80 also contains a calponin homology domain (CHD) that increa...
journal_title:Molecular biology of the cell
pub_type: 杂志文章
doi:10.1091/mbc.E10-07-0626
更新日期:2011-04-15 00:00:00
abstract::Previous research has found that a gamma-tubulin mutation in Schizosaccharomyces pombe is synthetically lethal with a deletion of the C-terminal motor domain kinesin-like protein gene pkl1, but the lethality of the double mutant prevents a phenotypic analysis of the synthetic interaction. We have investigated interact...
journal_title:Molecular biology of the cell
pub_type: 杂志文章
doi:10.1091/mbc.12.10.3161
更新日期:2001-10-01 00:00:00
abstract::The last steps of multivesicular body (MVB) formation, human immunodeficiency virus (HIV)-1 budding and cytokinesis require a functional endosomal sorting complex required for transport (ESCRT) machinery to facilitate topologically equivalent membrane fission events. Increased sodium tolerance (IST) 1, a new positive ...
journal_title:Molecular biology of the cell
pub_type: 杂志文章
doi:10.1091/mbc.e08-05-0474
更新日期:2009-03-01 00:00:00
abstract::The inositol 1,4,5-trisphosphate receptor (IP3R) is an intracellular calcium channel involved in coupling cell membrane receptors to calcium signal transduction pathways within cells including endocrine cells. Several isoforms (I, II, and III) of IP3Rs have been identified, which are encoded by separate genes, and are...
journal_title:Molecular biology of the cell
pub_type: 杂志文章
doi:10.1091/mbc.7.6.949
更新日期:1996-06-01 00:00:00
abstract::MicroRNAs (miRNAs), the tiny regulatory RNAs, form complexes with Argonaute (Ago) proteins and inhibit gene expression in metazoan cells. While studying parasite-invaded macrophages, we identify a unique mode of gene regulation in which the parasite Leishmania donovani (Ld) causes mitochondrial depolarization, reduces...
journal_title:Molecular biology of the cell
pub_type: 杂志文章
doi:10.1091/mbc.E16-06-0388
更新日期:2017-07-15 00:00:00
abstract::LLCPK-1 cells were transfected with a green fluorescent protein (GFP)-alpha tubulin construct and a cell line permanently expressing GFP-alpha tubulin was established (LLCPK-1alpha). The mitotic index and doubling time for LLCPK-1alpha were not significantly different from parental cells. Quantitative immunoblotting s...
journal_title:Molecular biology of the cell
pub_type: 杂志文章
doi:10.1091/mbc.12.4.971
更新日期:2001-04-01 00:00:00
abstract::Activation of the high-osmolarity glycerol (HOG) pathway for osmoregulation in the yeast Saccharomyces cerevisiae involves interaction of the adaptor Ste50p with the cytoplasmic tail of single-transmembrane protein Opy2p. We have determined the solution structure of the Ste50p-RA (Ras association) domain, and it shows...
journal_title:Molecular biology of the cell
pub_type: 杂志文章
doi:10.1091/mbc.e09-07-0645
更新日期:2009-12-01 00:00:00
abstract::Genes occupy preferred spatial positions within interphase cell nuclei. However, positioning patterns are not an innate feature of a locus, and genes can alter their localization in response to physiological and pathological changes. Here we screen the radial positioning patterns of 40 genes in normal, hyperplasic, an...
journal_title:Molecular biology of the cell
pub_type: 杂志文章
doi:10.1091/mbc.E15-05-0280
更新日期:2016-01-15 00:00:00
abstract::Survivin, a subunit of the chromosome passenger complex (CPC), binds the N-terminal tail of histone H3, which is phosphorylated on T3 by Haspin kinase, and localizes the complex to the inner centromeres. We used x-ray crystallography to determine the residues of Survivin that are important in binding phosphomodified h...
journal_title:Molecular biology of the cell
pub_type: 杂志文章
doi:10.1091/mbc.E11-11-0904
更新日期:2012-04-01 00:00:00
abstract::Clathrin-mediated endocytosis is a fundamental cellular process conserved from yeast to mammals and is an important endocytic route for the internalization of many specific cargos, including activated growth factor receptors. Here we examined changes in tyrosine phosphorylation, a representative output of growth facto...
journal_title:Molecular biology of the cell
pub_type: 杂志文章
doi:10.1091/mbc.E10-07-0637
更新日期:2011-02-15 00:00:00
abstract::The secretory and autophagy pathways can be thought of as the biosynthetic (i.e., anabolic) and degradative (i.e., catabolic) branches of the endomembrane system. In analogy to anabolic and catabolic pathways in metabolism, there is mounting evidence that the secretory and autophagy pathways are intimately linked and ...
journal_title:Molecular biology of the cell
pub_type: 杂志文章,评审
doi:10.1091/mbc.E16-11-0762
更新日期:2017-05-01 00:00:00
abstract::The kinesin superfamily of microtubule motor proteins is important in many cellular processes, including mitosis and meiosis, vesicle transport, and the establishment and maintenance of cell polarity. We have characterized two related kinesins in fission yeast, klp5+ and klp6+,, that are amino-terminal motors of the K...
journal_title:Molecular biology of the cell
pub_type: 杂志文章
doi:10.1091/mbc.12.12.3919
更新日期:2001-12-01 00:00:00
abstract::The intestinal cells of Caenorhabditis elegans embryos contain prominent, birefringent gut granules that we show are lysosome-related organelles. Gut granules are labeled by lysosomal markers, and their formation is disrupted in embryos depleted of AP-3 subunits, VPS-16, and VPS-41. We define a class of gut granule lo...
journal_title:Molecular biology of the cell
pub_type: 杂志文章
doi:10.1091/mbc.e05-01-0060
更新日期:2005-07-01 00:00:00