TACE is required for the activation of the EGFR by TGF-α in tumors
TACE is required for the activation of the EGFR by TGF-α in tumors
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DOI：
10.1093/emboj/cdg111
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发表时间：
2003-03-03
期刊：
影响因子：
11.4
通讯作者：
Arribas, J
中科院分区：
文献类型：
--
作者：
Borrell-Pagès, M;Rojo, F;Arribas, J
在表皮生长因子（EGFR）受体和相关受体的激活后传递细胞内信号的因素和机制被合理地充分理解，并且事实上是抗肿瘤药物的靶点。相比之下，对发送激活这些受体的信号所涉及的机制知之甚少。在这里，我们表明，当其蛋白水解脱落被阻止，跨膜形式的转化生长因子-α（proTGF-α）相互作用，但不激活，EGFR。因此，脱落似乎不仅控制可溶形式的生长因子（TGF-α）的可用性，而且控制跨膜形式的活性。负责proTGF-α脱落的蛋白酶（肿瘤坏死因子-α转化酶（TACE））的活性是体内EGFR活化和裸鼠肿瘤发展所必需的，表明TACE在肿瘤发生中的关键作用。与这一观点一致，TACE在分析的大多数乳腺肿瘤中显著过表达。总的来说，这些证据表明TACE是一种有前途的抗肿瘤治疗靶点。
The factors and mechanisms that transduce the intracellular signals sent upon activation of the receptor for the epidermal growth factor (EGFR) and related receptors are reasonably well understood and, in fact, are the targets of anti-tumor drugs. In contrast, less is known about the mechanisms implicated in sending the signals that activate these receptors. Here we show that when its proteolytic shedding is prevented, the transmembrane form of the transforming growth factor-alpha (proTGF-alpha) interacts with, but does not activate, the EGFR. Thus, shedding seems to control not only the availability of the soluble form of the growth factor (TGF-alpha) but also the activity of the transmembrane form. The activity of the protease responsible for the shedding of proTGF-alpha, tumor necrosis factor-alpha converting enzyme (TACE), is required for the activation of the EGFR in vivo and for the development of tumors in nude mice, indicating a crucial role of TACE in tumorigenesis. In agreement with this view, TACE is dramatically overexpressed in the majority of mammary tumors analyzed. Collectively, this evidence points to TACE as a promising target of anti-tumor therapy.