Membrane-anchored growth factor, HB-EGF, on the cell surface targeted to the inner nuclear membrane

Miki Hieda, Mayumi Isokane, Michiko Koizumi, Chiduru Higashi, Taro Tachibana, Masachika Shudou, Tomohiko Taguchi, Yohki Hieda, Shigeki Higashiyama

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74 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)763-769
Number of pages7
JournalJournal of Cell Biology
Issue number4
Publication statusPublished - 2008 Feb 25


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