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First published online October 22, 2008
doi: 10.1242/10.1242/jcs.031443

Journal of Cell Science 121, 3608-3618 (2008)
Published by The Company of Biologists 2008
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Research Article

Plasma-membrane-anchored growth factor pro-amphiregulin binds A-type lamin and regulates global transcription

Mayumi Isokane1,2, Miki Hieda1, Satoshi Hirakawa3, Masachika Shudou4, Koichi Nakashiro2, Koji Hashimoto3, Hiroyuki Hamakawa2 and Shigeki Higashiyama1,5,*

1 Department of Biochemistry and Molecular Genetics, Ehime University Graduate School of Medicine, Toon, Ehime 791-0295, Japan
2 Department of Oral and Maxillofacial Surgery, Ehime University Graduate School of Medicine, Toon, Ehime 791-0295, Japan
3 Department of Dermatology, Ehime University Graduate School of Medicine, Toon, Ehime 791-0295, Japan
4 Department of Bioscience, INCS, Ehime University Graduate School of Medicine, Toon, Ehime 791-0295, Japan
5 Protein Network Laboratory, CEREM, Ehime University Graduate School of Medicine, Toon, Ehime 791-0295, Japan

* Author for correspondence (e-mail: shigeki{at}m.ehime-u.ac.jp)

Accepted 5 August 2008

Amphiregulin (AR), a member of the EGF family, is synthesized as a type I transmembrane protein precursor (proAR) and expressed on the cell surface. Shedding of proAR yields a transmembrane-cytoplasmic fragment (AR-CTF), as well as a soluble AR. Here we demonstrate that the proAR-shedding stimuli trigger endocytosis of both AR-CTF and un-shed proAR. ProAR translocates from the plasma membrane to the inner nuclear membrane, whereas AR-CTF is translocated to the lysosome via retrograde membrane trafficking. Nuclear envelope localization of proAR involves truncation of the C-terminus, which subsequently activates the ER-retrieval signal. The truncated form of proAR interacts with A-type lamin and is retained at the inner nuclear membrane. Heterochromatin formation is then induced and global transcription is transiently suppressed. This study gives new insight into epigenetic chromatin organization in mammalian cells: a plasma-membrane-anchored growth factor is targeted to the inner nuclear membrane where it participates in dynamic chromatin organization and control of transcription.

Key words: Amphiregulin, Heterochromatin, Inner nuclear membrane, Lamin, RNA polymerase II transcription






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