Mice with defects in HB-EGF ectodomain shedding show severe developmental abnormalities

doi:10.1083/jcb.200307035

Published online 3 November 2003. doi:10.1083/jcb.200307035

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© The Rockefeller University Press, 0021-9525/2003/11/469 $8.00
The Journal of Cell Biology, Volume 163, Number 3, 469-475

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Mice with defects in HB-EGF ectodomain shedding show severe developmental abnormalities

Satoru Yamazaki¹, Ryo Iwamoto¹, Kazuko Saeki², Masanori Asakura³, Seiji Takashima³, Ayano Yamazaki¹, Rina Kimura¹, Hiroto Mizushima¹, Hiroki Moribe¹, Shigeki Higashiyama⁶, Masayuki Endoh⁴, Yasufumi Kaneda⁴, Satoshi Takagi⁵, Satoshi Itami⁵, Naoki Takeda⁷, Gen Yamada⁷ and Eisuke Mekada¹

¹ Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan
² Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan
³ Department of Internal Medicine and Therapeutics, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan
⁴ Division of Gene Therapy Science, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan
⁵ Department of Dermatology, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan
⁶ Department of Medical Biochemistry, Ehime University School of Medicine, Ehime 791-0295, Japan
⁷ Center for Animal Resource and Development and Graduate School of Molecular and Genomic Pharmacy, Kumamoto University, Kumamoto 860-0811, 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: emekada{at}biken.osaka-u.ac.jp

Heparin-binding EGF-like growth factor (HB-EGF) is first synthesizedas 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, expressingeither an uncleavable form (HB^uc) or a transmembrane domain–truncatedform (HB^tm) of the molecule. HB^uc/uc mice developed severe heartfailure and enlarged heart valves, phenotypes similar to thosein proHB-EGF null mice. On the other hand, mice carrying HB^tmexhibited severe hyperplasia in both skin and heart. These resultsindicate that ectodomain shedding of proHB-EGF is essentialfor HB-EGF function in vivo, and that this process requiresstrict control.

Key Words: ectodomain shedding; ErbB; cardiomyopathy; valvulogenesis; epidermal hyperplasia

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-anchoredform of HB-EGF; sHB-EGF, soluble form of HB-EGF; TPA, O-tetradecanoylphorbol-13-acetate;tRA, all-trans retinoic acid.

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