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 (HBΔtm) of the molecule. HBuc/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 HBΔtm 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.
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10 November 2003
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November 03 2003
Mice with defects in HB-EGF ectodomain shedding show severe developmental abnormalities
Satoru Yamazaki,
Satoru Yamazaki
1Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan
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Ryo Iwamoto,
Ryo Iwamoto
1Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan
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Kazuko Saeki,
Kazuko Saeki
2Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan
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Masanori Asakura,
Masanori Asakura
3Department of Internal Medicine and Therapeutics, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan
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Seiji Takashima,
Seiji Takashima
3Department of Internal Medicine and Therapeutics, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan
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Ayano Yamazaki,
Ayano Yamazaki
1Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan
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Rina Kimura,
Rina Kimura
1Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan
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Hiroto Mizushima,
Hiroto Mizushima
1Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan
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Hiroki Moribe,
Hiroki Moribe
1Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan
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Shigeki Higashiyama,
Shigeki Higashiyama
6Department of Medical Biochemistry, Ehime University School of Medicine, Ehime 791-0295, Japan
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Masayuki Endoh,
Masayuki Endoh
4Division of Gene Therapy Science, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan
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Yasufumi Kaneda,
Yasufumi Kaneda
4Division of Gene Therapy Science, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan
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Satoshi Takagi,
Satoshi Takagi
5Department of Dermatology, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan
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Satoshi Itami,
Satoshi Itami
5Department of Dermatology, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan
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Naoki Takeda,
Naoki Takeda
7Center for Animal Resource and Development and Graduate School of Molecular and Genomic Pharmacy, Kumamoto University, Kumamoto 860-0811, Japan
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Gen Yamada,
Gen Yamada
7Center for Animal Resource and Development and Graduate School of Molecular and Genomic Pharmacy, Kumamoto University, Kumamoto 860-0811, Japan
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Eisuke Mekada
Eisuke Mekada
1Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan
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Satoru Yamazaki
1Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan
Ryo Iwamoto
1Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan
Kazuko Saeki
2Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan
Masanori Asakura
3Department of Internal Medicine and Therapeutics, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan
Seiji Takashima
3Department of Internal Medicine and Therapeutics, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan
Ayano Yamazaki
1Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan
Rina Kimura
1Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan
Hiroto Mizushima
1Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan
Hiroki Moribe
1Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan
Shigeki Higashiyama
6Department of Medical Biochemistry, Ehime University School of Medicine, Ehime 791-0295, Japan
Masayuki Endoh
4Division of Gene Therapy Science, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan
Yasufumi Kaneda
4Division of Gene Therapy Science, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan
Satoshi Takagi
5Department of Dermatology, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan
Satoshi Itami
5Department of Dermatology, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan
Naoki Takeda
7Center for Animal Resource and Development and Graduate School of Molecular and Genomic Pharmacy, Kumamoto University, Kumamoto 860-0811, Japan
Gen Yamada
7Center for Animal Resource and Development and Graduate School of Molecular and Genomic Pharmacy, Kumamoto University, Kumamoto 860-0811, Japan
Eisuke Mekada
1Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan
Address correspondence to Eisuke Mekada, Department of Cell Biology, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan. Tel.: 81-6-6879-8286. Fax: 81-6-6879-8289. email: [email protected]
S. Yamazaki and R. Iwamoto contributed equally to this work.
The online version of this article includes supplemental material.
Abbreviations used in this paper: EGFR, EGF receptor; HB-EGF, heparin-binding EGF-like growth factor; proHB-EGF, membrane-anchored form of HB-EGF; sHB-EGF, soluble form of HB-EGF; TPA, O-tetradecanoylphorbol-13-acetate; tRA, all-trans retinoic acid.
Received:
July 07 2003
Accepted:
September 12 2003
Online ISSN: 1540-8140
Print ISSN: 0021-9525
The Rockefeller University Press
2003
J Cell Biol (2003) 163 (3): 469–475.
Article history
Received:
July 07 2003
Accepted:
September 12 2003
Citation
Satoru Yamazaki, Ryo Iwamoto, Kazuko Saeki, Masanori Asakura, Seiji Takashima, Ayano Yamazaki, Rina Kimura, Hiroto Mizushima, Hiroki Moribe, Shigeki Higashiyama, Masayuki Endoh, Yasufumi Kaneda, Satoshi Takagi, Satoshi Itami, Naoki Takeda, Gen Yamada, Eisuke Mekada; Mice with defects in HB-EGF ectodomain shedding show severe developmental abnormalities . J Cell Biol 10 November 2003; 163 (3): 469–475. doi: https://doi.org/10.1083/jcb.200307035
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