Lysophosphatidic Acid-Induced EGFR Transactivation Promotes Gastric Cancer Cell DNA Replication by Stabilizing Geminin in the S Phase.
Lysophosphatidic Acid-Induced EGFR Transactivation Promotes Gastric Cancer Cell DNA Replication by Stabilizing Geminin in the S Phase.
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DOI：
10.3389/fphar.2021.706240
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发表时间：
2021
影响因子：
5.6
通讯作者：
Fan L
中科院分区：
文献类型：
--
作者：
Zhao H;Gezi G;Tian X;Jia P;Morigen M;Fan L
Geminin是DNA复制许可因子、染色质许可因子和DNA复制因子（Cdt）1的抑制剂，对维持基因组完整性至关重要。作为一种多功能蛋白，双生蛋白也参与肿瘤的进展，但分子细节在很大程度上是未知的。在这里，我们发现溶血磷脂酸（LPA）诱导的geminin上调是特异性的胃癌细胞。LPA通过LPA受体（LPAR）3和基质金属蛋白酶（MMPs）信号转导，反式激活表皮生长因子受体（EGFR）（Y1173），从而稳定S期的geminin表达水平。LPA还诱导去泛素化蛋白（DUB）3的表达，这阻止了双生蛋白的降解。这些结果揭示了胃癌进展的一种新机制，该机制涉及通过LPA诱导的EGFR反式激活来调节双生蛋白的稳定性，并为信号通路和肿瘤细胞特异性抑制剂提供了潜在的靶点。
Geminin, an inhibitor of the DNA replication licensing factor, chromatin licensing and DNA replication factor (Cdt) 1, is essential for the maintenance of genomic integrity. As a multifunctional protein, geminin is also involved in tumor progression, but the molecular details are largely unknown. Here, we found that lysophosphatidic acid (LPA)–induced upregulation of geminin was specific to gastric cancer cells. LPA acted via LPA receptor (LPAR) 3 and matrix metalloproteinases (MMPs) signaling to transactivate epidermal growth factor receptor (EGFR) (Y1173) and thereby stabilize geminin expression level during the S phase. LPA also induced the expression of deubiquitinating protein (DUB) 3, which prevented geminin degradation. These results reveal a novel mechanism underlying gastric cancer progression that involves the regulation of geminin stability by LPA-induced EGFR transactivation and provide potential targets for the signaling pathway and tumor cell–specific inhibitors.
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DOI：
10.1098/rstb.2011.0073
发表时间：
2011-12-27
期刊：
Philosophical transactions of the Royal Society of London. Series B, Biological sciences
影响因子：
--
作者：
Diffley JF
通讯作者：
Diffley JF
影响因子：
7.3
作者：
Gonzalez, MA;Tachibana, KK;Coleman, N
通讯作者：
Coleman, N
影响因子：
11.4
作者：
Ballabeni, A;Melixetian, M;Helin, K
通讯作者：
Helin, K
影响因子：
11.4
作者：
Gschwind, A;Hart, S;Ullrich, A
通讯作者：
Ullrich, A
影响因子：
9.7
作者：
Alsahafi, Elham Nafea;Thavaraj, Selvam;Tavassoli, Mahvash
通讯作者：
Tavassoli, Mahvash