Proteolytic release of the carboxy-terminal fragment of proHB-EGF causes nuclear export of PLZF.
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.
Nanba
Daisuke
D
Department of Medical Biochemistry, Ehime University School of Medicine, Onsen-gun, Ehime 791-0295, Japan.
Mammoto
Akiko
A
Hashimoto
Koji
K
Higashiyama
Shigeki
S
D021581:Active Transport, Cell Nucleus / Q000235:genetics*; D000818:Animals; D002460:Cell Line; D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism*; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism*; D019925:Cyclin A / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004815:Epidermal Growth Factor / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005809:Genes, Regulator / Q000235:genetics; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D006965:Hyperplasia / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D036341:Intercellular Signaling Peptides and Proteins; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism; D051741:Kruppel-Like Transcription Factors; D051379:Mice; D008810:Mice, Inbred C57BL; D010447:Peptide Hydrolases / Q000235:genetics / Q000378:metabolism; D000075722:Promyelocytic Leukemia Zinc Finger Protein; D011498:Protein Precursors / Q000378:metabolism; D017434:Protein Structure, Tertiary / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics; D016196:S Phase / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D012867:Skin / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
D019925:Cyclin A; D004268:DNA-Binding Proteins; C587883:HBEGF protein, human; C587884:Hbegf protein, mouse; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D051741:Kruppel-Like Transcription Factors; D000075722:Promyelocytic Leukemia Zinc Finger Protein; D011498:Protein Precursors; D012097:Repressor Proteins; D014157:Transcription Factors; C513267:Zbtb16 protein, mouse; C092037:ZBTB16 protein, human; D004815:Epidermal Growth Factor; D010447:Peptide Hydrolases