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

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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 PKCδ binds in vivo and in vitro to the cytoplasmic domain of MDC9/meltrin‐γ/ADAM9, a member of the metalloprotease–disintegrin family. Furthermore, the presence of constitutively active PKCδ or MDC9 results in the shedding of the ectodomain of proHB‐EGF, whereas MDC9 mutants lacking the metalloprotease domain, as well as kinase‐negative PKCδ, suppress the TPA‐induced shedding of the ectodomain. These results suggest that MDC9 and PKCδ are involved in the stimulus‐coupled shedding of the proHB‐EGF ectodomain.