A metalloprotease-disintegrin, MDC9/meltrin-gamma/ADAM9 and PKC delta 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 f actor (HB-EGF) that exists in a membrane-anchored form which is converted t o a soluble form upon cell stimulation with TPA, an activator of protein ki nase C (PKC), We show that PKC delta binds in vivo and in vitro to the cyto plasmic domain of MDC9/meltrin-gamma/ADAM9, a member of the metalloprotease -disintegrin family. Furthermore, the presence of constitutively active PKC delta or MDC9 results in the shedding of the ectodomain of proHB-EGF, wher eas MDC9 mutants lacking the metalloprotease domain, as well as kinase-nega tive PKC delta, suppress the TPA-induced shedding of the ectodomain. These results suggest that MDC9 and PKC delta are involved in the stimulus-couple d shedding of the proHB-EGF ectodomain.