TACE cleavage of proamphiregulin regulates GPCR-induced proliferation and motility of cancer cells
TACE cleavage of proamphiregulin regulates GPCR-induced proliferation and motility of cancer cells
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DOI：
10.1093/emboj/cdg231
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发表时间：
2003-05-15
期刊：
影响因子：
11.4
通讯作者：
Ullrich, A
中科院分区：
文献类型：
--
作者：
Gschwind, A;Hart, S;Ullrich, A
G蛋白偶联受体（GPCR）和表皮生长因子受体（EGFR）信号系统之间的通信涉及EGF样前体的细胞表面蛋白水解。然而，EGFR信号转导通路的潜在机制在很大程度上是未知的。我们证明，在鳞状细胞癌细胞，刺激与GPCR激动剂LPA或卡巴胆碱特异性导致金属蛋白酶切割和双调蛋白（AR）的释放。此外，通过siRNA沉默AR基因或通过中和抗体和肝素抑制AR生物活性可防止GPCR诱导的EGFR酪氨酸磷酸化、下游促有丝分裂信号传导事件、细胞增殖、迁移和存活介导物Akt/PKB的活化。因此，尽管EGF家族配体之间存在一些功能冗余，但本研究揭示了AR在GPCR触发的细胞反应中的独特和重要作用。此外，我们提出的证据表明，金属蛋白酶-去整合素肿瘤坏死因子-α转换酶（TACE）的金属蛋白酶-3，显性阴性TACE突变体或RNA干扰的组织抑制剂的封锁抑制GPCR刺激的AR释放，EGFR激活和下游事件。因此，TACE可以作为GPCR介导的信号传导的效应物发挥作用，并代表细胞受体串扰网络的关键要素。
Communication between G protein-coupled receptor (GPCR) and epidermal growth factor receptor (EGFR) signalling systems involves cell surface proteolysis of EGF-like precursors. The underlying mechanisms of EGFR signal transactivation pathways, however, are largely unknown. We demonstrate that in squamous cell carcinoma cells, stimulation with the GPCR agonists LPA or carbachol specifically results in metalloprotease cleavage and release of amphiregulin (AR). Moreover, AR gene silencing by siRNA or inhibition of AR biological activity by neutralizing antibodies and heparin prevents GPCR-induced EGFR tyrosine phosphorylation, downstream mitogenic signalling events, cell proliferation, migration and activation of the survival mediator Akt/PKB. Therefore, despite some functional redundancy among EGF family ligands, the present study reveals a distinct and essential role for AR in GPCR-triggered cellular responses. Furthermore, we present evidence that blockade of the metalloprotease-disintegrin tumour necrosis factor-alpha-converting enzyme (TACE) by the tissue inhibitor of metalloprotease-3, a dominant-negative TACE mutant or RNA interference suppresses GPCR-stimulated AR release, EGFR activation and downstream events. Thus, TACE can function as an effector of GPCR-mediated signalling and represents a key element of the cellular receptor cross-talk network.