A dual signaling cascade that regulates the ectodomain shedding of heparin-binding epidermal growth factor-like growth factor.
Ectodomain shedding is an important mechanism to regulate the biological activities of membrane proteins. We focus here on the signaling mechanism of the ectodomain shedding of heparin-binding epidermal growth factor (EGF)-like growth factor (pro HB-EGF). Lysophosphatidic acid (LPA), a ligand for seven-transmembrane G protein-coupled receptors, stimulates the shedding of pro HB-EGF, which constitutes a G protein-coupled receptor-mediated transactivation of the EGF receptor. Experiments using a series of inhibitors and overexpression of mutant forms of signaling molecules revealed that the Ras-Raf-MEK signal is essential for the LPA-induced shedding. In addition, the small GTPase Rac is involved in the LPA-induced shedding, possibly to promote MEK activation. 12-O-Tetradecanoylphorbol-13-acetate is another potent inducer of pro HB-EGF shedding. We also demonstrate that the LPA-induced pathway is distinct from the 12-O-tetradecanoylphorbol-13-acetate-induced pathway and that these pathways constitute a dual signaling cascade that regulates the shedding of pro HB-EGF.
Umata
T
T
Institute of Life Science, Kurume University, Kurume, Fukuoka 839-0861, Japan.
Hirata
M
M
Takahashi
T
T
Ryu
F
F
Shida
S
S
Takahashi
Y
Y
Tsuneoka
M
M
Miura
Y
Y
Masuda
M
M
Horiguchi
Y
Y
Mekada
E
E
D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000737:chemistry* / Q000378:metabolism*; D020558:GTP Phosphohydrolases / Q000378:metabolism; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D008246:Lysophospholipids / Q000494:pharmacology*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D008954:Models, Biological; D009154:Mutation; D010957:Plasmids / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D017434:Protein Structure, Tertiary; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000737:chemistry* / Q000378:metabolism*; D015398:Signal Transduction; D013755:Tetradecanoylphorbol Acetate; D013997:Time Factors; D015533:Transcriptional Activation; D014162:Transfection; D014709:Vero Cells; D000077191:Wortmannin; D018631:ras Proteins / Q000378:metabolism
D000730:Androstadienes; D004791:Enzyme Inhibitors; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D008246:Lysophospholipids; D011956:Receptors, Cell Surface; D004815:Epidermal Growth Factor; D019908:Proto-Oncogene Proteins c-raf; D011493:Protein Kinase C; D020929:Mitogen-Activated Protein Kinase Kinases; D020558:GTP Phosphohydrolases; D018631:ras Proteins; D013755:Tetradecanoylphorbol Acetate; D000077191:Wortmannin