hMENA is a key regulator in endothelin-1/β-arrestin1-induced invadopodial function and metastatic process.
hMENA is a key regulator in endothelin-1/β-arrestin1-induced invadopodial function and metastatic process.
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DOI：
10.1073/pnas.1715998115
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发表时间：
2018-03-20
影响因子：
11.1
通讯作者：
Rosanò L
中科院分区：
文献类型：
--
作者：
Di Modugno F;Caprara V;Chellini L;Tocci P;Spadaro F;Ferrandina G;Sacconi A;Blandino G;Nisticò P;Bagnato A;Rosanò L
发现转移扩散的新靶点和新决定因素是卵巢癌中未满足的需求，卵巢癌受高复发率的困扰。内皮素-1受体（ET-1 R），属于G-蛋白偶联受体家族，是恶性肿瘤进展的重要靶点。在此，我们通过与多功能蛋白β-arrestin 1（β-arr 1）的特异性相互作用，确定了ET-1 R与肌动蛋白调节蛋白hMENA/hMENAΔv6之间的机制联系，β-arr 1启动信号级联反应，作为侵袭足成熟和恶性播散的分子复合物的一部分。通过使用马昔腾坦（一种美国食品药品监督管理局批准的抗肺动脉高压药物）靶向ET-1 R可损害控制卵巢癌进展的β-arr 1介导的信号网络，因此代表了卵巢癌患者的一种治疗选择。内皮素-1受体（ET-1 R）的异常激活可激发与肿瘤进展相关的多效性效应。该受体激活的网络可能是由β-arrestin 1（β-arr 1）驱动的相互作用体精细地、空间地和暂时地协调的。在这里，我们确定hMENA，肌动蛋白调节蛋白ENA/VASP家族的成员，作为β-arr 1的相互作用伴侣，在浆液性卵巢癌（SOC）进展中ET-1 R下游的侵袭足功能所必需。ET-1激活ET-1 R通过β-arr 1上调hMENA/hMENAΔv6亚型的表达，仅限于间充质样侵袭性SOC细胞。β-arr 1与hMENA/hMENAΔv6的相互作用由ET-1触发，导致RhoC和coronin的激活，膜1型基质金属蛋白酶的募集和侵袭伪足的成熟，从而增强细胞可塑性，跨内皮迁移和侵袭细胞的扩散。ET-1 R拮抗剂马昔腾坦给药损害了β-arr 1与hMENA的相互作用，并抑制了SOC原位异种移植物中的侵袭足成熟和肿瘤播散。最后，高ETAR/hMENA/β-arr 1基因表达特征与SOC患者的不良预后相关。这些数据确定了hMENA/hMENAΔv6在ET-1/β-arr 1诱导的侵袭性伪足活性和卵巢癌进展中的关键作用。
Discovering new targets and novel determinants of metastatic spread is an unmet need in ovarian cancer, which is plagued by high rates of recurrence. Endothelin-1 receptors (ET-1R), belonging to the G-protein–coupled receptor family, represent important targets critically involved in malignant progression. Here we identify a mechanistic link between ET-1R and the actin regulatory protein hMENA/hMENAΔv6 through the specific interaction with the multifunctional protein β-arrestin1 (β-arr1), which initiates signaling cascades as part of the molecular complex crucial for invadopodial maturation and malignant dissemination. Targeting ET-1R by using macitentan, a Food and Drug Administration-approved antipulmonary arterial hypertension drug, can impair the β-arr1–mediated signaling network controlling ovarian cancer progression and therefore represents a therapeutic option for ovarian cancer patients. Aberrant activation of endothelin-1 receptors (ET-1R) elicits pleiotropic effects relevant for tumor progression. The network activated by this receptor might be finely, spatially, and temporarily orchestrated by β-arrestin1 (β-arr1)–driven interactome. Here, we identify hMENA, a member of the actin-regulatory protein ENA/VASP family, as an interacting partner of β-arr1, necessary for invadopodial function downstream of ET-1R in serous ovarian cancer (SOC) progression. ET-1R activation by ET-1 up-regulates expression of hMENA/hMENAΔv6 isoforms through β-arr1, restricted to mesenchymal-like invasive SOC cells. The interaction of β-arr1 with hMENA/hMENAΔv6 triggered by ET-1 leads to activation of RhoC and cortactin, recruitment of membrane type 1-matrix metalloprotease, and invadopodia maturation, thereby enhancing cell plasticity, transendothelial migration, and the resulting spread of invasive cells. The treatment with the ET-1R antagonist macitentan impairs the interaction of β-arr1 with hMENA and inhibits invadopodial maturation and tumor dissemination in SOC orthotopic xenografts. Finally, high ETAR/hMENA/β-arr1 gene expression signature is associated with a poor prognosis in SOC patients. These data define a pivotal function of hMENA/hMENAΔv6 for ET-1/β-arr1–induced invadopodial activity and ovarian cancer progression.
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DOI：
10.1038/nrm3141
发表时间：
2011-06-23
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
通讯作者：
--
影响因子：
64.5
作者：
Gertler, FB;Niebuhr, K;Soriano, P
通讯作者：
Soriano, P
影响因子：
8
作者：
Rosano, L.;Cianfrocca, R.;Bagnato, A.
通讯作者：
Bagnato, A.
影响因子：
9.2
作者：
Bravo-Cordero, Jose Javier;Oser, Matthew;Chen, Xiaoming;Eddy, Robert;Hodgson, Louis;Condeelis, John
通讯作者：
Condeelis, John
影响因子：
7.2
作者：
Melchionna R;Iapicca P;Di Modugno F;Trono P;Sperduti I;Fassan M;Cataldo I;Rusev BC;Lawlor RT;Diodoro MG;Milella M;Grazi GL;Bissell MJ;Scarpa A;Nisticò P
通讯作者：
Nisticò P