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
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
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DOI：
10.1093/emboj/17.24.7260
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发表时间：
1998-12-15
期刊：
影响因子：
11.4
通讯作者：
Mekada, E
中科院分区：
文献类型：
--
作者：
Izumi, Y;Hirata, M;Mekada, E
位于细胞表面的许多蛋白质的胞外域在细胞刺激时脱落。一种这样的蛋白质是肝素结合EGF样生长因子（HB-EGF），其以膜锚定形式存在，其在用蛋白激酶C（PKC）的激活剂TPA刺激细胞后转化为可溶性形式。我们表明，PKC δ在体内和体外结合至MDC 9/meltrin-gamma/ADAM 9的胞质结构域，所述MDC 9/meltrin-gamma/ADAM 9是金属蛋白酶-去整合素家族的成员。此外，组成型活性PKC δ或MDC 9的存在导致proHB-EGF的胞外结构域脱落，而缺乏金属蛋白酶结构域的MDC 9突变体以及激酶阴性PKC δ抑制TPA诱导的胞外结构域脱落。这些结果表明，MDC 9和PKC δ参与了proHB-EGF胞外域的刺激偶联脱落。
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 PKC delta 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 PKC delta or MDC9 results in the shedding of the ectodomain of proHB-EGF, whereas MDC9 mutants lacking the metalloprotease domain, as well as kinase-negative PKC delta, suppress the TPA-induced shedding of the ectodomain. These results suggest that MDC9 and PKC delta are involved in the stimulus-coupled shedding of the proHB-EGF ectodomain.