Mice with defects in HB-EGF ectodomain shedding show severe developmental abnormalities.
Heparin-binding EGF-like growth factor (HB-EGF) is first synthesized as a membrane-anchored form (proHB-EGF), and its soluble form (sHB-EGF) is released by ectodomain shedding from proHB-EGF. To examine the significance of proHB-EGF processing in vivo, we generated mutant mice by targeted gene replacement, expressing either an uncleavable form (HBuc) or a transmembrane domain-truncated form (HBdeltatm) of the molecule. HB(uc/uc) mice developed severe heart failure and enlarged heart valves, phenotypes similar to those in proHB-EGF null mice. On the other hand, mice carrying HBdeltatm exhibited severe hyperplasia in both skin and heart. These results indicate that ectodomain shedding of proHB-EGF is essential for HB-EGF function in vivo, and that this process requires strict control.
Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan.
Satoru
S
Yamazaki
Ryo
R
Iwamoto
Kazuko
K
Saeki
Masanori
M
Asakura
Seiji
S
Takashima
Ayano
A
Yamazaki
Rina
R
Kimura
Hiroto
H
Mizushima
Hiroki
H
Moribe
Shigeki
S
Higashiyama
Masayuki
M
Endoh
Yasufumi
Y
Kaneda
Satoshi
S
Takagi
Satoshi
S
Itami
Naoki
N
Takeda
Gen
G
Yamada
Eisuke
E
Mekada
D000818:Animals; D022081:Cell Surface Extensions / Q000235:genetics / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000172:deficiency* / Q000235:genetics; D018390:Gene Targeting; D006330:Heart Defects, Congenital / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006351:Heart Valves / Q000002:abnormalities / Q000473:pathology; D066257:Heparin-binding EGF-like Growth Factor; D006965:Hyperplasia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D036341:Intercellular Signaling Peptides and Proteins; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation / Q000235:genetics; D011499:Protein Processing, Post-Translational / Q000235:genetics; D017434:Protein Structure, Tertiary / Q000235:genetics; D012868:Skin Abnormalities / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D012995:Solubility
C587884:Hbegf protein, mouse; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D004815:Epidermal Growth Factor