Membrane-anchored growth factor, HB-EGF, on the cell surface targeted to the inner nuclear membrane.
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.
Hieda
Miki
M
Department of Biochemistry and Molecular Genetics, Ehime University Graduate School of Medicine, Ehime 791-0295, Japan.
Isokane
Mayumi
M
Koizumi
Michiko
M
Higashi
Chiduru
C
Tachibana
Taro
T
Shudou
Masachika
M
Taguchi
Tomohiko
T
Hieda
Yohki
Y
Higashiyama
Shigeki
S
D021581:Active Transport, Cell Nucleus / Q000502:physiology; D000818:Animals; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism* / Q000648:ultrastructure; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism / Q000648:ultrastructure; D004705:Endocytosis / Q000502:physiology*; D005110:Extracellular Space / Q000378:metabolism; D005260:Female; D019204:GTP-Binding Proteins / Q000235:genetics; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D009685:Nuclear Envelope / Q000378:metabolism* / Q000648:ultrastructure; D017434:Protein Structure, Tertiary / Q000502:physiology; D021381:Protein Transport / Q000502:physiology; D051381:Rats; D011921:Rats, Inbred WKY; D050436:Regulatory Elements, Transcriptional / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D020696:rab5 GTP-Binding Proteins / Q000235:genetics
C587883:HBEGF protein, human; C587885:Hbegf protein, rat; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D012097:Repressor Proteins; C118779:rab11 binding protein, Bos taurus; D019204:GTP-Binding Proteins; D020696:rab5 GTP-Binding Proteins