A metalloprotease-disintegrin, MDC9/meltrin-gamma/ADAM9 and PKCdelta are involved in TPA-induced ectodomain shedding of membrane-anchored heparin-binding EGF-like growth factor.
The ectodomains of many proteins located at the cell surface are shed upon cell stimulation. One such protein is the heparin-binding EGF-like growth factor (HB-EGF) that exists in a membrane-anchored form which is converted to a soluble form upon cell stimulation with TPA, an activator of protein kinase C (PKC). We show that PKCdelta binds in vivo and in vitro to the cytoplasmic domain of MDC9/meltrin-gamma/ADAM9, a member of the metalloprotease-disintegrin family. Furthermore, the presence of constitutively active PKCdelta or MDC9 results in the shedding of the ectodomain of proHB-EGF, whereas MDC9 mutants lacking the metalloprotease domain, as well as kinase-negative PKCdelta, suppress the TPA-induced shedding of the ectodomain. These results suggest that MDC9 and PKCdelta are involved in the stimulus-coupled shedding of the proHB-EGF ectodomain.
Izumi
Y
Y
Department of Molecular Biology, Yokohama City University School of Medicine 3-9, Fuku-ura, Kanagawa-ku, Yokohama 236-0004, Japan.
Hirata
M
M
Hasuwa
H
H
Iwamoto
R
R
Umata
T
T
Miyado
K
K
Tamai
Y
Y
Kurisaki
T
T
Sehara-Fujisawa
A
A
Ohno
S
S
Mekada
E
E
D051722:ADAM Proteins; D020134:Catalytic Domain / Q000235:genetics; D019483:Disintegrins / Q000235:genetics / Q000378:metabolism*; D004815:Epidermal Growth Factor / Q000378:metabolism*; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D007527:Isoenzymes / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008666:Metalloendopeptidases / Q000378:metabolism*; D009124:Muscle Proteins / Q000378:metabolism; D009154:Mutation; D011485:Protein Binding; D011493:Protein Kinase C / Q000378:metabolism*; D051745:Protein Kinase C-delta; D011498:Protein Precursors / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D011994:Recombinant Proteins / Q000378:metabolism; D012995:Solubility; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*
D019483:Disintegrins; C587883:HBEGF protein, human; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D007527:Isoenzymes; D008565:Membrane Proteins; D009124:Muscle Proteins; D011498:Protein Precursors; D011994:Recombinant Proteins; D004815:Epidermal Growth Factor; D011493:Protein Kinase C; D051745:Protein Kinase C-delta; D051722:ADAM Proteins; C098339:ADAM9 protein, human; D008666:Metalloendopeptidases; D013755:Tetradecanoylphorbol Acetate