Myofibroblast differentiation by transforming growth factor-β1 is dependent on cell adhesion and integrin signaling via focal adhesion kinase

被引:492
作者
Thannickal, VJ
Lee, DY
White, ES
Cui, Z
Larios, JM
Chacon, R
Horowitz, JC
Day, RM
Thomas, PE
机构
[1] Univ Michigan, Sch Med, Div Pulm & Crit Care Med, Dept Internal Med,Med Ctr, Ann Arbor, MI 48109 USA
[2] Tufts Univ, New England Med Ctr, Div Pulm & Crit Care, Dept Med, Boston, MA 02111 USA
关键词
D O I
10.1074/jbc.M208544200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Myofibroblast differentiation and activation by transforming growth factor-beta1 (TGF-beta1) is a critical event in the pathogenesis of human fibrotic diseases, but regulatory mechanisms for this effect are unclear. In this report, we demonstrate that stable expression of the myofibroblast phenotype requires both TGF-beta1 and adhesion-dependent signals. TGF-beta1-induced myofibroblast differentiation of lung fibroblasts is blocked in non-adherent cells despite the preservation of TGF-beta receptor(s)-mediated signaling of Smad2 phosphorylation. TGF-beta1 induces tyrosine phosphorylation of focal adhesion kinase (FAK) including that of its autophosphorylation site, Tyr-397, an effect that is dependent on cell adhesion and is delayed relative to early Smad signaling. Pharmacologic inhibition of FAR or expression of kinase-deficient FAK, mutated by substituting Tyr-397 with Phe, inhibit TGF-beta1-induced alpha-smooth muscle actin expression, stress fiber formation, and cellular hypertrophy. Basal expression of a-smooth muscle actin is elevated in cells grown on fibronectin-coated dishes but is decreased on laminin and poly-D-lysine, a nonintegrin binding polypeptide. TGF-beta1 up-regulates expression of integrins and fibronectin, an effect that is associated with autophosphorylation/activation of FAK. Thus, a safer and more effective therapeutic strategy for fibrotic diseases characterized by persistent myofibroblast activation may be to target this integrin/FAK pathway while not interfering with tumor-suppressive functions of TGF-beta1/Smad signaling.
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收藏
页码:12384 / 12389
页数:6
相关论文
共 39 条
[1]   AN ASSAY FOR TRANSFORMING GROWTH-FACTOR-BETA USING CELLS TRANSFECTED WITH A PLASMINOGEN-ACTIVATOR INHIBITOR-1 PROMOTER LUCIFERASE CONSTRUCT [J].
ABE, M ;
HARPEL, JG ;
METZ, CN ;
NUNES, I ;
LOSKUTOFF, DJ ;
RIFKIN, DB .
ANALYTICAL BIOCHEMISTRY, 1994, 216 (02) :276-284
[2]  
ADAMS JC, 1993, DEVELOPMENT, V117, P1183
[3]   The compliance of collagen gels regulates transforming growth factor-β induction of α-smooth muscle actin in fibroblasts [J].
Arora, PD ;
Narani, N ;
McCulloch, CAG .
AMERICAN JOURNAL OF PATHOLOGY, 1999, 154 (03) :871-882
[4]  
BORDER WA, 1994, NEW ENGL J MED, V331, P1286
[5]   TRANSFORMING GROWTH-FACTOR-BETA REGULATES THE SPLICING PATTERN OF FIBRONECTIN MESSENGER-RNA PRECURSOR [J].
BORSI, L ;
CASTELLANI, P ;
RISSO, AM ;
LEPRINI, A ;
ZARDI, L .
FEBS LETTERS, 1990, 261 (01) :175-178
[6]   Phosphorylation of tyrosine 397 in focal adhesion kinase is required for binding phosphatidylinositol 3-kinase [J].
Chen, HC ;
Appeddu, PA ;
Isoda, H ;
Guan, JL .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1996, 271 (42) :26329-26334
[7]   TRANSFORMING GROWTH-FACTOR-BETA-1 INDUCES ALPHA-SMOOTH MUSCLE ACTIN EXPRESSION IN GRANULATION-TISSUE MYOFIBROBLASTS AND IN QUIESCENT AND GROWING CULTURED FIBROBLASTS [J].
DESMOULIERE, A ;
GEINOZ, A ;
GABBIANI, F ;
GABBIANI, G .
JOURNAL OF CELL BIOLOGY, 1993, 122 (01) :103-111
[8]  
Dugina V, 2001, J CELL SCI, V114, P3285
[9]  
Finlay GA, 2000, J BIOL CHEM, V275, P27650
[10]   PRESENCE OF MODIFIED FIBROBLASTS IN GRANULATION TISSUE AND THEIR POSSIBLE ROLE IN WOUND CONTRACTION [J].
GABBIANI, G ;
RYAN, GB ;
MAJNO, G .
EXPERIENTIA, 1971, 27 (05) :549-&