Published online February 25, 2008
doi:10.1083/jcb.200710022
The Journal of Cell Biology, Vol. 180, No. 4, 763-769
The Rockefeller University Press, 0021-9525 $30.00
© 2008 Hieda et al.
Membrane-anchored growth factor, HB-EGF, on the cell surface targeted to the inner nuclear membrane
Miki Hieda1,
Mayumi Isokane1,
Michiko Koizumi1,
Chiduru Higashi4,
Taro Tachibana4,
Masachika Shudou2,
Tomohiko Taguchi5,
Yohki Hieda6, and
Shigeki Higashiyama1,3
1 Department of Biochemistry and Molecular Genetics, 2 Department of Bioscience, INCS, and 3 Protein Network Laboratory, CEREM, Ehime University Graduate School of Medicine, Ehime 791-0295, Japan
4 Department of Bioengineering, Graduate School of Engineering, Osaka City University, Osaka 558-8585, Japan
5 Department of Biochemistry, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan
6 Department of Biology, Osaka Dental University, Osaka 573-1121, Japan
Correspondence to Shigeki Higashiyama: shigeki{at}m.ehime-u.ac.jp
Heparin-binding EGF-like growth factor (HB-EGF) is synthesized as a type I transmembrane protein (proHB-EGF) and expressed on the cell surface. The ectodomain shedding of proHB-EGF at the extracellular region on the plasma membrane yields a soluble EGF receptor ligand and a transmembrane-cytoplasmic fragment (HB-EGF-CTF). The cytoplasmic domain of proHB-EGF (HB-EGF-cyto) interacts with transcriptional repressors to reverse their repressive activities. However, how HB-EGF-cyto accesses transcriptional repressors is yet unknown. The present study demonstrates that, after exposure to shedding stimuli, both HB-EGF-CTF and unshed proHB-EGF translocate to the nuclear envelope. Immunoelectron microscopy and digitonin-permeabilized cells showed that HB-EGF-cyto signals are at the inner nuclear membrane. A short sequence element within the HB-EGF-cyto allows a transmembrane protein to localize to the nuclear envelope. The dominant-active form of Rab5 and Rab11 suppressed nuclear envelope targeting. Collectively, these data demonstrate that membrane-anchored HB-EGF is targeted to the inner nuclear membrane via a retrograde membrane trafficking pathway.
Abbreviations used in this paper: Bcl6, B-cell lymphoma 6; HB-EGF, heparin-binding EGF-like growth factor; INM, inner nuclear membrane; LAP2β, lamina-associated polypeptide 2β; NE, nuclear envelope; ONM, outer nuclear membrane; PLZF, promyelocytic leukemia zinc finger protein; TPA, phorbol ester 12-O-tetradecanoylphorbol-13-acetate.
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