The elevated lysophosphatidic acid signaling has been causally linked to cancer-associated inflammation and tumorigenesis through upregulation of nuclear factor-κB signaling. However, how this signaling event is regulated has not yet been fully understood. Here we demonstrate that TRIP6, an LPA2 receptor-interacting adaptor protein, functions as a positive regulator of nuclear factor-κB and JNK signaling through direct binding to and activation of the E3 ligase TRAF6. Upon lysophosphatidic acid stimulation, TRIP6 recruits TRAF6 to the LPA2 receptor and promotes lysophosphatidic acid-induced JNK and nuclear factor-κB activation in a TRAF6-dependent manner. TRIP6 antagonizes the recruitment of deubiquitinases A20 and CYLD to TRAF6, thus sustaining the E3 ligase activity of TRAF6 and augmenting lysophosphatidic acid-activated nuclear factor-κB signaling. In contrast, depletion of TRIP6 by TRIP6-specific shRNA or Cas9/sgRNA greatly enhances the association of TRAF6 with A20 and CYLD, and attenuates lysophosphatidic acid-induced muclear factor-κB and JNK/p38 activation in ovarian cancer cells. On the other hand, TRAF6 also regulates TRIP6 by facilitating its binding to nuclear factor-κB p65 and phosphorylation by c-Src. Together, TRIP6 cooperates with TRAF6 to regulate the LPA2 receptor signaling, which may ultimately contribute to chronic inflammation, apoptotic resistance and cell invasion.

中文翻译：

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TRIP6拮抗A20和CYLD向TRAF6的募集，以促进LPA2受体介导的TRAF6活化。

升高的溶血磷脂酸信号通过核因子-κB信号的上调与癌症相关的炎症和肿瘤发生有因果关系。然而，如何完全调节该信号转导事件尚未被完全理解。在这里，我们证明，与LPA2受体相互作用的衔接子蛋白TRIP6通过直接结合和激活E3连接酶TRAF6而起核因子-κB和JNK信号转导的正调节作用。溶血磷脂酸刺激后，TRIP6将TRAF6募集到LPA2受体，并以TRAF6依赖性方式促进溶血磷脂酸诱导的JNK和核因子-κB活化。TRIP6拮抗将去泛素酶A20和CYLD募集至TRAF6，因此维持了TRAF6的E3连接酶活性并增强了溶血磷脂酸激活的核因子-κB信号传导。相比之下，TRIP6特异的shRNA或Cas9 / sgRNA对TRIP6的消耗会大大增强TRAF6与A20和CYLD的结合，并减弱溶血磷脂酸诱导的核因子-κB和JNK / p38在卵巢癌细胞中的激活。另一方面，TRAF6还通过促进TRIP6与核因子κBp65的结合以及c-Src的磷酸化来调节TRIP6。TRIP6与TRAF6共同调节LPA2受体信号传导，这可能最终导致慢性炎症，凋亡抗性和细胞侵袭。并减弱溶血磷脂酸诱导的卵巢癌细胞中的核因子-κB和JNK / p38活化。另一方面，TRAF6还通过促进TRIP6与核因子κBp65的结合以及c-Src的磷酸化来调节TRIP6。TRIP6与TRAF6共同调节LPA2受体信号传导，这可能最终导致慢性炎症，凋亡抗性和细胞侵袭。并减弱溶血磷脂酸诱导的卵巢癌细胞中的核因子-κB和JNK / p38活化。另一方面，TRAF6还通过促进TRIP6与核因子κBp65的结合以及c-Src的磷酸化来调节TRIP6。TRIP6与TRAF6共同调节LPA2受体信号传导，这可能最终导致慢性炎症，凋亡抗性和细胞侵袭。