TIAM1 Antagonizes TAZ/YAP Both in the Destruction Complex in the Cytoplasm and in the Nucleus to Inhibit Invasion of Intestinal Epithelial Cells.
TIAM1 Antagonizes TAZ/YAP Both in the Destruction Complex in the Cytoplasm and in the Nucleus to Inhibit Invasion of Intestinal Epithelial Cells.
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DOI：
10.1016/j.ccell.2017.03.007
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发表时间：
2017-05-08
期刊：
影响因子：
50.3
通讯作者：
Malliri A
中科院分区：
文献类型：
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作者：
Diamantopoulou Z;White G;Fadlullah MZH;Dreger M;Pickering K;Maltas J;Ashton G;MacLeod R;Baillie GS;Kouskoff V;Lacaud G;Murray GI;Sansom OJ;Hurlstone AFL;Malliri A
异常的WNT信号转导驱动结直肠癌（CRC）。在这里，我们通过抑制WNT信号传导的效应物TAZ和雅普，将TIAM 1鉴定为CRC进展的关键拮抗剂。我们证明，TIAM 1穿梭于细胞质和细胞核之间，通过不同的机制拮抗TAZ/雅普。在细胞质中，TIAM 1定位于破坏复合物，并通过增强其与βTrCP的相互作用促进TAZ降解。核TIAM 1抑制TAZ/雅普与TEAD的相互作用，抑制涉及上皮-间质转化、细胞迁移和侵袭的TAZ/雅普靶基因的表达，并因此抑制CRC细胞迁移和侵袭。重要的是，临床标本中高核TIAM 1与CRC患者生存率增加相关。总之，我们的研究结果表明，在CRC中，TIAM 1通过调节雅普/TAZ活性来抑制肿瘤进展。TIAM 1是WNT调节的破坏复合物的一部分，其调节TAZ/雅普稳定性。WNT诱导TIAM 1核转位，其中其减少TAZ/YAP-TEAD相互作用。核TIAM 1阻断TAZ/雅普遗传程序，抑制CRC细胞的迁移。将TIAM 1鉴定为结直肠癌进展关键拮抗剂。细胞质TIAM 1通过增强TAZ与βTrCP的相互作用促进TAZ降解，而细胞核TIAM 1抑制TAZ/雅普与TEAD的相互作用，抑制TAZ/雅普靶基因的表达。
Aberrant WNT signaling drives colorectal cancer (CRC). Here, we identify TIAM1 as a critical antagonist of CRC progression through inhibiting TAZ and YAP, effectors of WNT signaling. We demonstrate that TIAM1 shuttles between the cytoplasm and nucleus antagonizing TAZ/YAP by distinct mechanisms in the two compartments. In the cytoplasm, TIAM1 localizes to the destruction complex and promotes TAZ degradation by enhancing its interaction with βTrCP. Nuclear TIAM1 suppresses TAZ/YAP interaction with TEADs, inhibiting expression of TAZ/YAP target genes implicated in epithelial-mesenchymal transition, cell migration, and invasion, and consequently suppresses CRC cell migration and invasion. Importantly, high nuclear TIAM1 in clinical specimens associates with increased CRC patient survival. Together, our findings suggest that in CRC TIAM1 suppresses tumor progression by regulating YAP/TAZ activity. TIAM1 is part of the WNT-regulated destruction complex regulating TAZ/YAP stability WNT induces TIAM1 nuclear translocation where it reduces TAZ/YAP-TEAD interaction Nuclear TIAM1 blocks the TAZ/YAP genetic program inhibiting migration of CRC cells Nuclear TIAM1 predicts good prognosis in CRC Diamantopoulou et al. identify TIAM1 as a critical antagonist of colorectal cancer progression. Cytoplasmic TIAM1 promotes TAZ degradation by enhancing its interaction with βTrCP whereas nuclear TIAM1 suppresses TAZ/YAP interaction with TEADs, inhibiting expression of TAZ/YAP target genes.