title: Transforming growth factor β1 (TGFβ1) regulates CD44V6 expression and activity through extracellular signal-regulated kinase (ERK)-induced EGR1 in pulmonary fibrogenic fibroblasts.
abstract: The appearance of myofibroblasts is generally thought to be the underlying cause of the fibrotic changes that underlie idiopathic pulmonary fibrosis. However, the cellular/molecular mechanisms that account for the fibroblast-myofibroblast differentiation/activation in idiopathic pulmonary fibrosis remain poorly understood. We investigated the functional role of hyaluronan receptor CD44V6 (CD44 containing variable exon 6 (v6)) for differentiation of lung fibroblast to myofibroblast phenotype. Increased hyaluronan synthesis and CD44 expression have been detected in numerous fibrotic organs. Previously, we found that the TGFβ1/CD44V6 pathway is important in lung myofibroblast collagen-1 and α-smooth-muscle actin synthesis. Because increased EGR1 (early growth response-1) expression has been shown to appear very early and nearly coincident with the expression of CD44V6 found after TGFβ1 treatment, we investigated the mechanism(s) of regulation of CD44V6 expression in lung fibroblasts by TGFβ1. TGFβ1-mediated CD44V6 up-regulation was initiated through EGR1 via ERK-regulated transcriptional activation. We showed that TGFβ1-induced CD44V6 expression is through EGR1-mediatedAP-1(activator protein-1) activity and that theEGR1- andAP-1-binding sites in theCD44v6promoter account for its responsiveness to TGFβ1 in lung fibroblasts. We also identified a positive-feedback loop in which ERK/EGR1 signaling promotes CD44V6 splicing and found that CD44V6 then sustains ERK signaling, which is important forAP-1activity in lung fibroblasts. Furthermore, we identified thatHAS2-produced hyaluronan is required for CD44V6 and TGFβRI co-localization and subsequent CD44V6/ERK1/EGR1 signaling. These results demonstrate a novel positive-feedback loop that links the myofibroblast phenotype to TGFβ1-stimulated CD44V6/ERK/EGR1 signaling.
authors.affiliation: From the Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, South Carolina 29425, ghatak@musc.edu.
authors.forename: Shibnath
authors.initials: S
authors.lastname: Ghatak
authors.affiliation: From the Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, South Carolina 29425.
authors.forename: Roger R
authors.initials: RR
authors.lastname: Markwald
authors.affiliation: the Department of Biomedical Engineering, Cleveland Clinic, Cleveland, Ohio 44195.
authors.forename: Vincent C
authors.initials: VC
authors.lastname: Hascall
authors.affiliation: From the Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, South Carolina 29425.|the College of Charleston, Charleston, South Carolina 29424.
authors.forename: William
authors.initials: W
authors.lastname: Dowling
authors.affiliation: the Departments of Pediatrics-Neonatology and.
authors.forename: Robyn Grayson
authors.initials: RG
authors.lastname: Lottes
authors.affiliation: the Departments of Pediatrics-Neonatology and.
authors.forename: John E
authors.initials: JE
authors.lastname: Baatz
authors.affiliation: Drug Discovery and Biomedical sciences, Medical University of South Carolina, Charleston, South Carolina 29425.
authors.forename: Gyada
authors.initials: G
authors.lastname: Beeson
authors.affiliation: Drug Discovery and Biomedical sciences, Medical University of South Carolina, Charleston, South Carolina 29425.
authors.forename: Craig C
authors.initials: CC
authors.lastname: Beeson
authors.affiliation: the Division of Pulmonary and Critical Care Medicine, Department of Medicine, and the Department of Pediatric Newborn Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, and.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Perrella
authors.affiliation: the Division of Pulmonary, Allergy, and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35294-0006.
authors.forename: Victor J
authors.initials: VJ
authors.lastname: Thannickal
authors.affiliation: From the Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, South Carolina 29425, misra@musc.edu.
authors.forename: Suniti
authors.initials: S
authors.lastname: Misra
mesh_terms: D000818:Animals; D051766:Early Growth Response Protein 1 / Q000378:metabolism*; D005786:Gene Expression Regulation; D014453:Glucuronosyltransferase / Q000378:metabolism; D018960:Hyaluronan Receptors / Q000096:biosynthesis*; D000076002:Hyaluronan Synthases; D006820:Hyaluronic Acid / Q000096:biosynthesis; D008168:Lung / Q000378:metabolism* / Q000473:pathology; D020935:MAP Kinase Signaling System; D051379:Mice; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D058628:Myofibroblasts / Q000378:metabolism* / Q000473:pathology; D011658:Pulmonary Fibrosis / Q000378:metabolism* / Q000473:pathology; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*
chemical_list: C112697:CD44v6 antigen; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D018960:Hyaluronan Receptors; C508961:Tgfb1 protein, mouse; D053773:Transforming Growth Factor beta1; D006820:Hyaluronic Acid; D014453:Glucuronosyltransferase; C491099:Has2 protein, mouse; D000076002:Hyaluronan Synthases; D048052:Mitogen-Activated Protein Kinase 3
keywords: AP-1 transcription factor (AP-1); CD44; early growth response protein 1 (EGR1); extracellular-signal-regulated kinase (ERK); signaling