Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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ADAM Proteins
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Catalytic Domain / genetics
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Disintegrins / genetics
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Disintegrins / metabolism*
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Epidermal Growth Factor / metabolism*
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Heparin-binding EGF-like Growth Factor
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Intercellular Signaling Peptides and Proteins
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Isoenzymes / metabolism*
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Membrane Proteins / genetics
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Membrane Proteins / metabolism*
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Metalloendopeptidases / metabolism*
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Muscle Proteins / metabolism
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Mutation
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Protein Binding
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Protein Kinase C / metabolism*
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Protein Kinase C-delta
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Protein Precursors / metabolism
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Protein Processing, Post-Translational
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Recombinant Proteins / metabolism
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Solubility
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Tetradecanoylphorbol Acetate / pharmacology*
Substances
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Disintegrins
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HBEGF protein, human
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Heparin-binding EGF-like Growth Factor
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Intercellular Signaling Peptides and Proteins
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Isoenzymes
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Membrane Proteins
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Muscle Proteins
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Protein Precursors
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Recombinant Proteins
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Epidermal Growth Factor
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Protein Kinase C
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Protein Kinase C-delta
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ADAM Proteins
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ADAM9 protein, human
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Metalloendopeptidases
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Tetradecanoylphorbol Acetate