Heparin-binding EGF-like growth factor and ErbB signaling is essential for heart function

Ryo Iwamoto, Satoru Yamazaki, Masanori Asakura, Seiji Takashima, Hidetoshi Hasuwa, Kenji Miyado, Satoshi Adachi, Masafumi Kitakaze, Koji Hashimoto, Gerhard Raab, Daisuke Nanba, Shigeki Higashiyama, Masatsugu Hori, Michael Klagsbrun, Eisuke Mekada

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307 Citations (Scopus)


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 (HBdel/del) were generated to examine the role of HB-EGF in vivo. More than half of the HBdel/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, HBdel/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 HBdel/del hearts. It was concluded that HB-EGF activation of receptor tyrosine kinases is essential for normal heart function.

Original languageEnglish
Pages (from-to)3221-3226
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number6
Publication statusPublished - 2003 Mar 18
Externally publishedYes

ASJC Scopus subject areas

  • General


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