title: Isoform-specific regulation of the actin-organizing protein palladin during TGF-beta1-induced myofibroblast differentiation.
abstract: Contractile myofibroblasts are responsible for remodeling of extracellular matrix during wound healing; however, their continued activity results in various fibrocontractive diseases. Conversion of fibroblasts into myofibroblasts is induced by transforming growth factor-beta1 (TGF-beta1) and is hallmarked by the neo-expression of alpha-smooth muscle actin (alpha-SMA), a commonly used myofibroblast marker. Moreover, myofibroblast differentiation and acquisition of the contractile phenotype involves functionally important alterations in the expression of actin-organizing proteins. We investigated whether myofibroblast differentiation is accompanied by changes in the expression of palladin, a cytoskeletal protein that controls stress fiber integrity. Palladin is expressed as several isoforms, including major 3Ig (90 kDa) and 4Ig (140 kDa) forms that differ in their N-terminal sequence. Expression of the 4Ig isoform is strongly induced in fibroblast stress fibers upon TGF-beta1 treatment preceding alpha-SMA upregulation. TGF-beta1 induced upregulation of palladin is mediated both by Smad and mitogen-activated protein kinase pathways. Furthermore, palladin 4Ig-isoform is co-expressed with alpha-SMA in vivo in experimental rat wounds and in human myofibroblast-containing lesions. Taken together these results identify palladin 4Ig as a novel marker of myofibroblast conversion in vitro and in vivo. They also provide for the first time information about the signaling cascades involved in the regulation of palladin expression.
authors.affiliation: Neuroscience Program and Department of Pathology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland. mikko.ronty@helsinki.fi
authors.forename: Mikko J
authors.initials: MJ
authors.lastname: Rönty
authors.forename: Suvi-Katri
authors.initials: SK
authors.lastname: Leivonen
authors.forename: Boris
authors.initials: B
authors.lastname: Hinz
authors.forename: Andrew
authors.initials: A
authors.lastname: Rachlin
authors.forename: Carol A
authors.initials: CA
authors.lastname: Otey
authors.forename: Veli-Matti
authors.initials: VM
authors.lastname: Kähäri
authors.forename: Olli M
authors.initials: OM
authors.lastname: Carpén
mesh_terms: D000199:Actins / Q000032:analysis / Q000378:metabolism; D000818:Animals; D000906:Antibodies / Q000276:immunology; D002454:Cell Differentiation; D003598:Cytoskeletal Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D015870:Gene Expression; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D032390:Myoblasts, Smooth Muscle / Q000737:chemistry / Q000166:cytology / Q000378:metabolism*; D010750:Phosphoproteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D020033:Protein Isoforms / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D051381:Rats; D012867:Skin / Q000737:chemistry / Q000293:injuries / Q000378:metabolism; D051900:Smad3 Protein / Q000235:genetics / Q000378:metabolism; D022502:Stress Fibers / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology; D015854:Up-Regulation; D014945:Wound Healing; D014947:Wounds and Injuries / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000199:Actins; D000906:Antibodies; D003598:Cytoskeletal Proteins; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D010750:Phosphoproteins; D020033:Protein Isoforms; D051900:Smad3 Protein; D053773:Transforming Growth Factor beta1; D048051:p38 Mitogen-Activated Protein Kinases; C412722:PALLD protein, human; C498862:Acta2 protein, rat