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