A metalloprotease-disintegrin, MDC9/meltrin-γ/ADAM9 and PKCδ 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 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.