Heparin-binding EGF-like growth factor and ErbB signaling is essential for heart function.
The heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF) is a member of the EGF family of growth factors that binds to and activates the EGF receptor (EGFR) and the related receptor tyrosine kinase, ErbB4. HB-EGF-null mice (HB(del/del)) were generated to examine the role of HB-EGF in vivo. More than half of the HB(del/del) mice died in the first postnatal week. The survivors developed severe heart failure with grossly enlarged ventricular chambers. Echocardiographic examination showed that the ventricular chambers were dilated and that cardiac function was diminished. Moreover, HB(del/del) mice developed grossly enlarged cardiac valves. The cardiac valve and the ventricular chamber phenotypes resembled those displayed by mice lacking EGFR, a receptor for HB-EGF, and by mice conditionally lacking ErbB2, respectively. HB-EGF-ErbB interactions in the heart were examined in vivo by administering HB-EGF to WT mice. HB-EGF induced tyrosine phosphorylation of ErbB2 and ErbB4, and to a lesser degree, of EGFR in cardiac myocytes. In addition, constitutive tyrosine phosphorylation of both ErbB2 and ErbB4 was significantly reduced in HB(del/del) hearts. It was concluded that HB-EGF activation of receptor tyrosine kinases is essential for normal heart function.
Iwamoto
Ryo
R
Department of Cell Biology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan.
Yamazaki
Satoru
S
Asakura
Masanori
M
Takashima
Seiji
S
Hasuwa
Hidetoshi
H
Miyado
Kenji
K
Adachi
Satoshi
S
Kitakaze
Masafumi
M
Hashimoto
Koji
K
Raab
Gerhard
G
Nanba
Daisuke
D
Higashiyama
Shigeki
S
Hori
Masatsugu
M
Klagsbrun
Michael
M
Mekada
Eisuke
E
D000818:Animals; D004815:Epidermal Growth Factor / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D066246:ErbB Receptors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D005260:Female; D018390:Gene Targeting; D006321:Heart / Q000502:physiology*; D006330:Heart Defects, Congenital / Q000235:genetics / Q000473:pathology; D006351:Heart Valves / Q000002:abnormalities; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D066247:Receptor, ErbB-4; D015398:Signal Transduction
D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D066247:Receptor, ErbB-4; C587884:Hbegf protein, mouse; C587690:Erbb4 protein, mouse