Department of Medicine, Section of Hematology/Oncology, Baylor College of Medicine, Houston, Texas, USA.
Mol Cell Biol. 2013 Apr;33(7):1394-409. doi: 10.1128/MCB.01149-12. Epub 2013 Jan 22.
TRIP6 is an adaptor protein that regulates cell motility and antiapoptotic signaling. Although it has been implicated in tumorigenesis, the underlying mechanism remains largely unknown. Here we provide evidence that TRIP6 promotes tumorigenesis by serving as a bridge to promote the recruitment of p27(KIP1) to AKT in the cytosol. TRIP6 regulates the membrane translocation and activation of AKT and facilitates AKT-mediated recognition and phosphorylation of p27(KIP1) specifically at T157, thereby promoting the cytosolic mislocalization of p27(KIP1). This is required for p27(KIP1) to enhance lysophosphatidic acid (LPA)-induced ovarian cancer cell migration. TRIP6 also promotes serum-induced reduction of nuclear p27(KIP1) expression levels through Skp2-dependent and -independent mechanisms. Consequently, knockdown of TRIP6 in glioblastoma or ovarian cancer xenografts restores nuclear p27(KIP1) expression and impairs tumor proliferation. As TRIP6 is upregulated in gliomas and its levels correlate with poor clinical outcomes in a dose-dependent manner, it may represent a novel prognostic marker and therapeutic target in gliomas.
TRIP6 是一种衔接蛋白，可调节细胞运动和抗凋亡信号。虽然它已被牵连到肿瘤发生中，但潜在的机制在很大程度上仍然未知。在这里，我们提供的证据表明，TRIP6 通过充当桥接物促进 p27(KIP1) 在细胞质中募集到 AKT，从而促进肿瘤发生。TRIP6 调节 AKT 的膜易位和激活，并促进 AKT 介导的对 p27(KIP1)的特异性识别和磷酸化，特别是在 T157 处，从而促进 p27(KIP1)在细胞质中的定位错误。这对于 p27(KIP1)增强溶血磷脂酸 (LPA)诱导的卵巢癌细胞迁移是必需的。TRIP6 还通过 Skp2 依赖和非依赖机制促进血清诱导的核 p27(KIP1)表达水平降低。因此，在神经胶质瘤或卵巢癌异种移植瘤中敲低 TRIP6 可恢复核 p27(KIP1)表达并损害肿瘤增殖。由于 TRIP6 在神经胶质瘤中上调，并且其水平与不良的临床结果呈剂量依赖性相关，因此它可能代表神经胶质瘤中的一种新的预后标志物和治疗靶标。
