Izumi Y, Hirata M, Hasuwa H, Iwamoto R, Umata T, Miyado K, Tamai Y, Kurisaki T, Sehara-Fujisawa A, Ohno S, Mekada E
Department of Molecular Biology, Yokohama City University School of Medicine 3-9, Fuku-ura, Kanagawa-ku, Yokohama 236-0004, Japan.
EMBO J. 1998 Dec 15;17(24):7260-72. doi: 10.1093/emboj/17.24.7260.
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.
许多位于细胞表面的蛋白质的胞外域在细胞受到刺激时会脱落。其中一种蛋白质是肝素结合表皮生长因子样生长因子（HB-EGF），它以膜锚定形式存在，在用蛋白激酶C（PKC）的激活剂佛波酯（TPA）刺激细胞后会转化为可溶性形式。我们发现PKCδ在体内和体外均与金属蛋白酶-解整合素家族成员MDC9/溶基质素γ/ADAM9的胞质域结合。此外，组成型活性PKCδ或MDC9的存在会导致前体HB-EGF胞外域的脱落，而缺乏金属蛋白酶结构域的MDC9突变体以及激酶阴性的PKCδ则会抑制TPA诱导的胞外域脱落。这些结果表明，MDC9和PKCδ参与了前体HB-EGF胞外域的刺激偶联脱落过程。
