Isoform-specific regulation of the actin-organizing protein palladin during TGF-beta1-induced myofibroblast differentiation.
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.
Rönty
Mikko J
MJ
Neuroscience Program and Department of Pathology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland. mikko.ronty@helsinki.fi
Leivonen
Suvi-Katri
SK
Hinz
Boris
B
Rachlin
Andrew
A
Otey
Carol A
CA
Kähäri
Veli-Matti
VM
Carpén
Olli M
OM
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
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