Treatment of quiescent cultures mouse embryo-derived AKR-2B cells with transforming growth factor beta resulted in an early induction c-sis mRNA. The increase mRNA was followed by a corresponding protein similar to platelet-derived (PDGF) the culture medium. In addition, PDGF-regulated genes (c-fos and c-myc) were stimulated delayed kinetics relative that seen other cell systems direct PDGF stimulation. A model is proposed which monolayer mitogenicity mediated subsequent autocrine...

Idiopathic pulmonary fibrosis is a progressive and fatal fibrotic disease of the lungs with unclear etiology. Prior efforts to treat idiopathic that focused on anti-inflammatory therapy have not proven be effective. Recent insight suggests pathogenesis mediated through foci dysregulated fibroblasts driven by profibrotic cytokine signaling. TGF-β PDGF are 2 most potent these cytokines. In current study, we investigated role TGF-β–induced activation Abelson (Abl) tyrosine kinase. Our data...

Idiopathic pulmonary fibrosis is a progressive and fatal fibrotic disease of the lungs with unclear etiology. Prior efforts to treat idiopathic that focused on anti-inflammatory therapy have not proven be effective. Recent insight suggests pathogenesis mediated through foci dysregulated fibroblasts driven by profibrotic cytokine signaling. TGF-β PDGF are 2 most potent these cytokines. In current study, we investigated role TGF-β–induced activation Abelson (Abl) tyrosine kinase. Our data...

Transforming growth factor-beta (TGF-beta) is the single most important cytokine promoting renal fibrogenesis. p21-activated kinase-2 (PAK2) and activation of abelson nonreceptor tyrosine kinase (c-abl) have been shown recently to be smad-independent, fibroblast-specific targets downstream activated TGF-beta receptor. In current study we show that in cultured NRK49F-renal fibroblasts (but not tubular or mesangial cells) similarly activates PAK2 as well c-abl induces cell proliferation....

Abstract Suramin, a polyanionic compound, has previously been shown to dissociate platelet‐derived growth factor (PDGF) from its receptor. In the present study suramin was found inhibit of sparse cultures AKR‐2B cells in fetal bovine serum (FBS)‐supplemented medium dose‐dependent, reversible fashion. Suramin also inhibited ability FBS, transforming β (TGFβ), heparin‐binding type‐2 (HBGF‐2), and epidermal (EGF) stimulate DNA synthesis density‐arrested cells. The inhibition factor‐stimulated...

Proteins in the transforming growth factor-beta (TGF-beta) family recognize transmembrane serine/threonine kinases known as type I and II receptors. Binding of TGF-beta to receptors results receptor down-regulation signaling. Whereas previous work has focused on activities controlling signaling, more recent studies have begun address trafficking properties In this report, it is shown that undergo recycling both presence absence ligand activation, with rates internalization being unaffected...

Transforming growth factor beta 1 (TGF 1) is a potent inhibitor of epithelial cell proliferation. We present data which indicate that proliferation inhibited when TGF added throughout the prereplicative G1 phase. Cultures become reversibly blocked in late at G1/S-phase boundary. The inhibitory effects on occur presence RNA synthesis 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole. Associated with this effect decrease phosphorylation and histone H1 kinase activity p34cdc2 protein kinase....

Abstract Transforming growth factor-β (TGF-β) stimulates cellular proliferation and transformation to a myofibroblast phenotype in vivo subset of fibroblast cell lines. As the Smad pathway is activated by TGF-β essentially all types, it unlikely be sole mediator type–specific outcomes stimulation. In current study, we determined that receptor signaling activates phosphatidylinositol 3-kinase (PI3K) several but not epithelial cultures independently Smad2 Smad3. PI3K activation occurs presence...

Members of the transforming growth factor β (TGF-β) family proteins signal through cell surface transmembrane serine/threonine protein kinases known as type I and II receptors. The TGF-β is extended phosphorylation receptor-associated Smad by receptor. Although numerous investigations have established sequence events in receptor (TGF-βR) activation, none examined role endocytic pathway initiation and/or maintenance signaling response. In this study we investigated whether TGF-βR...

PDGF-dependent hepatic stellate cell (HSC) recruitment is an essential step in liver fibrosis and the sinusoidal vascular changes that accompany this process. However, mechanisms regulate PDGF signaling remain incompletely defined. Here, we found two rat models of fibrosis, axonal guidance molecule neuropilin-1 (NRP-1) was upregulated activated HSCs, which exhibit highly motile myofibroblast phenotype. Additionally, NRP-1 colocalized with PDGF-receptor β (PDGFRβ) HSCs both injury human HSC...

TGF-β–dependent metabolic dysregulation contributes to lung fibrosis.

Transforming growth factor-beta (TGFβ) is an enigmatic protein with various roles in healthy tissue homeostasis/development as well the development or progression of cancer, wound healing, fibrotic disorders, and immune modulation, to name a few. As TGFβ causal fibroproliferative disorders featuring localized systemic tissue/organ fibrosis activated stroma observed malignancies, characterizing pathways players mediating its action fundamental. In current study, we found that induces...

Transforming growth factor β (TGF-β) causes arrest in epithelial cells and proliferation morphological transformation fibroblasts. Despite the ability of TGF-β to induce various cellular phenotypes, few discernible differences signaling between cell types have been reported, with only well-characterized pathway (the Smad cascade) seemingly under identical control. We determined that receptor activates STE20 homolog PAK2 mammalian cells. activation occurs fibroblast but not cultures is...

Renal interstitial fibrosis is a major determinant of renal failure in the majority chronic diseases. Transforming growth factor-beta (TGF-beta) single most important cytokine promoting fibrogenesis. Recent vitro studies identified novel non-smad TGF-beta targets including p21-activated kinase-2 (PAK2), abelson nonreceptor tyrosine kinase (c-Abl), and mammalian target rapamycin (mTOR) that are activated by mesenchymal cells, specifically fibroblasts but less epithelial cells. In present...

Abstract Stimulation of quiescent cultures AKR‐2B cells with transforming growth factor type β (TGFβ) resulted in a transitory increase actin cytoplasmic poly(A) + RNA. Levels mRNA peaked approximately 4–8 hours subsequent to TGFβ addition and approached basal levels by 24 hours. The accumulation transcripts was dose dependent insensitive inhibitors protein synthesis; 1–3 ng/ml induced maximal gene expression. Actin isotype‐specific probes demonstrated that both β‐ γ‐cytoplasmic actins are TGFβ.

In the tumor microenvironment, TGF-β induces transdifferentiation of quiescent pericytes and related stromal cells into myofibroblasts that promote growth metastasis. The mechanisms governing myofibroblastic activation remain poorly understood, its role in microenvironment has not been explored. Here, we demonstrate IQ motif containing GTPase activating protein 1 (IQGAP1) binds to receptor II (TβRII) suppresses TβRII-mediated signaling prevent differentiation microenvironment. We found...

Evidence is provided that the fibroproliferative actions of TGF-β are dependent on a metabolic adaptation sustains pathologic growth. Specifically, profibrotic signaling shown to require fatty acid synthase (FASN), an essential anabolic enzyme responsible for de novo synthesis acids. With use pharmacologic and genetic approaches, we show TGF-β-stimulated FASN expression independent Smad2/ 3 mediated via mammalian target rapamycin complex 1. In absence activity or protein, -driven fibrogenic...

TGF-β plays a central role in the pathogenesis of fibroproliferative disorders. Defining exact underlying molecular basis is therefore critical for development viable therapeutic strategies. Here, we show that expression facilitative glucose transporter 1 (GLUT1) induced by fibroblast lines and primary cells required profibrotic effects TGF-β. In addition, enhanced GLUT1 observed fibrotic areas lungs both patients with idiopathic pulmonary fibrosis mice are subjected to fibrosis-inducing...

Transforming growth factor-β (TGF-β) superfamily members regulate a wide range of biological processes by binding to two transmembrane serine/threonine kinase receptors, type I and II. We have previously shown that the internalization these receptors is inhibited K + depletion, cytosol acidification, or hypertonic medium, suggesting involvement clathrin-coated pits. However, clathrin-associated adaptor complex AP2 identity subunit binds were not known. Herein, we studied issues combining...