Integrins play a critical role in mechanical stress-induced p38 MAPK activation.
Mechanical stress activates various hypertrophic responses, including activation of mitogen-activated protein kinases (MAPKs) in cardiac myocytes. Stretch activated extracellular signal-regulated kinases partly through secreted humoral growth factors, including angiotensin II, whereas stretch-induced activation of c-Jun NH(2)-terminal kinases and p38 MAPK was independent of angiotensin II. In this study, we examined the role of integrin signaling in stretch-induced activation of p38 MAPK in cardiomyocytes of neonatal rats. Overexpression of the tumor suppressor PTEN, which inhibits outside-in integrin signaling, strongly suppressed stretch-induced activation of p38 MAPK. Overexpression of focal adhesion kinase (FAK) antagonized the effects of PTEN, and both tyrosine residues at 397 and 925 of FAK were necessary for its effects. Stretch induced tyrosine phosphorylation and activation of FAK and Src. Stretch-induced activation of p38 MAPK was abolished by overexpression of FAT and CSK, which are inhibitors of the FAK and Src families, respectively, and was suppressed by overexpression of a dominant-negative mutant of Ras. Mechanical stretch-induced increase in protein synthesis was suppressed by SB202190, a p38 MAPK inhibitor. These results suggest that mechanical stress activates p38 MAPK and induces cardiac hypertrophy through the integrin-FAK-Src-Ras pathway in cardiac myocytes.
Aikawa
Ryuichi
R
Department of Cardiovascular Medicine, University of Tokyo Graduate School of Medicine, Tokyo, Japan.
Nagai
Toshio
T
Kudoh
Sumiyo
S
Zou
Yunzeng
Y
Tanaka
Mariko
M
Tamura
Masahito
M
Akazawa
Hiroshi
H
Takano
Hiroyuki
H
Nagai
Ryozo
R
Komuro
Issei
I
D000818:Animals; D000831:Animals, Newborn; D000081247:CSK Tyrosine-Protein Kinase; D002478:Cells, Cultured; D004789:Enzyme Activation; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D006352:Heart Ventricles / Q000166:cytology / Q000201:enzymology; D016023:Integrins / Q000502:physiology*; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D051059:PTEN Phosphohydrolase; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013314:Stress, Mechanical; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D014443:Tyrosine / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases; D018631:ras Proteins / Q000378:metabolism; D019061:src-Family Kinases
D016023:Integrins; D025521:Tumor Suppressor Proteins; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496052:Ptk2 protein, rat; D019061:src-Family Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D010744:Phosphoric Monoester Hydrolases; D051059:PTEN Phosphohydrolase; D018631:ras Proteins