Constitutive phosphorylation of focal adhesion kinase is involved in the myofibroblast differentiation of scleroderma fibroblasts.
Most of the cultured scleroderma fibroblasts have been reported to be myofibroblasts that have the ability to express alpha smooth muscle actin (alphaSMA). It is reported that, in human lung fibroblasts, alphaSMA is induced by transforming growth factor-beta (TGF-beta), which requires focal adhesion kinase (FAK) phosphorylation on its Tyr-397 site. In this study, we investigated how alphaSMA expression is upregulated in cultured scleroderma fibroblasts. 4-amino-5-(4-chlorophenyl)-7-(butyl)pyrazolo[3,4-d]pyrimidine, which is a pharmacologic inhibitor of FAK/Src, markedly diminished upregulated alphaSMA expression in scleroderma fibroblasts as well as in normal fibroblasts stimulated with TGF-beta. Likewise, alphaSMA expression was significantly reduced in sclerderma fibroblasts transfected with kinase-deficient FAK mutant. FAK phosphorylation levels on Tyr-397 in scleroderma fibroblasts were significantly higher than those in normal fibroblasts. Both alphaSMA expression and FAK phosphorylation levels in scleroderma fibroblasts were markedly diminished by the treatment with TGF-beta antisense oligonucleotide. These results indicate that the constitutive phosphorylation of FAK, which is possibly because of the autocrine TGF-beta signaling, may play an important role in alphaSMA expression in scleroderma fibroblasts.
Mimura
Yoshihiro
Y
Department of Dermatology, Faculty of Medicine, University of Tokyo, Tokyo, Japan. IN-DER@h.u-tokyo.ac.jp
Ihn
Hironobu
H
Jinnin
Masatoshi
M
Asano
Yoshihide
Y
Yamane
Kenichi
K
Tamaki
Kunihiko
K
D000199:Actins / Q000235:genetics; D002454:Cell Differentiation; D002478:Cells, Cultured; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D006801:Humans; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D012595:Scleroderma, Systemic / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000502:physiology*
D000199:Actins; D016376:Oligonucleotides, Antisense; D009842:Oligopeptides; D016212:Transforming Growth Factor beta; C047981:arginyl-glycyl-aspartic acid; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496050:PTK2 protein, human