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Published online 3 November 2003. doi:10.1083/jcb.200303017
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© The Rockefeller University Press, 0021-9525/2003/11/489 $8.00
The Journal of Cell Biology, Volume 163, Number 3, 489-502

Article

Proteolytic release of the carboxy-terminal fragment of proHB-EGF causes nuclear export of PLZF



Daisuke Nanba1, Akiko Mammoto1, Koji Hashimoto2 and Shigeki Higashiyama1

1 Department of Medical Biochemistry, Ehime University School of Medicine, Ehime 791-0295, Japan
2 Department of Dermatology, Ehime University School of Medicine, Ehime 791-0295, Japan

Address correspondence to Shigeki Higashiyama, Dept. of Medical Biochemistry, Ehime University School of Medicine, Shitsukawa, Shigenobu-cho, Onsen-gun, Ehime 791-0295, Japan. Tel.: 81-89-960-5253. Fax: 81-89-960-5256. email: shigeki{at}m.ehime-u.ac.jp

Cleavage of membrane-anchored heparin-binding EGF-like growth factor (proHB-EGF) via metalloprotease activation yields amino- and carboxy-terminal regions (HB-EGF and HB-EGF-C, respectively), with HB-EGF widely recognized as a key element of epidermal growth factor receptor transactivation in G protein–coupled receptor signaling. Here, we show a biological role of HB-EGF-C in cells. Subsequent to proteolytic cleavage of proHB-EGF, HB-EGF-C translocated from the plasma membrane into the nucleus. This translocation triggered nuclear export of the transcriptional repressor, promyelocytic leukemia zinc finger (PLZF), which we identify as an HB-EGF-C binding protein. Suppression of cyclin A and delayed entry of S-phase in cells expressing PLZF were reversed by the production of HB-EGF-C. These results indicate that released HB-EGF-C functions as an intracellular signal and coordinates cell cycle progression with HB-EGF.

Key Words: HB-EGF; ADAM12; shedding; PLZF; transcriptional repression

A. Mammoto's present address is Department of Surgical Research, Children's Hospital, Boston, MA 02115.

Abbreviations used in this paper: ADAM, a disintegrin and metalloprotease; EGFR, epidermal growth factor receptor; GPCR, G protein–coupled receptor; HB-EGF, heparin-binding EGF-like growth factor; PLZF, promyelocytic leukemia zinc finger; proHB-EGF, membrane-anchored heparin-binding EGF-like growth factor; TPA, 12-O-tetradecanoylphorbol-13-acetate.


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