The Drosophila RASSF homolog antagonizes the hippo pathway.
The Drosophila RASSF homolog antagonizes the hippo pathway.
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DOI：
10.1016/j.cub.2006.10.060
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发表时间：
2006-12-19
期刊：
影响因子：
9.2
通讯作者：
Tapon, Nicolas
中科院分区：
文献类型：
--
作者：
Polesello, Cedric;Huelsmann, Sven;Brown, Nicholas H.;Tapon, Nicolas
正确的器官大小是由细胞死亡和增殖之间的平衡决定的。这种微妙的平衡被扰乱会导致癌症的形成。Hippo （Hpo）是MST1和MST2（哺乳动物不育20样1和2）的果蝇同源基因，是控制细胞死亡和增殖的信号通路的关键调节剂。到目前为止，该途径由两个Band 4.1蛋白，Expanded （Ex）和Merlin (Mer)，两个丝氨酸/苏氨酸激酶，Hpo和Warts (Wts)，支架蛋白Salvador （Sav）和Mats，以及转录辅激活因子Yorkie （Yki）组成。有人提出Ex和Mer作用于Hpo的上游，Hpo磷酸化并激活Wts。Wts使Yki磷酸化，从而抑制其活性，降低Yki靶基因如caspase抑制剂DIAP1和微RNA bantam的表达。然而，导致Hpo活化的机制仍然知之甚少。在哺乳动物细胞中，肿瘤抑制因子Ras关联家族（RASSF）的成员已被证明与MST1结合并调节其活性。在这项研究中，我们发现果蝇RASSF同源物（dRASSF）通过与Sav竞争结合Hpo来限制Hpo的活性。此外，我们观察到dRASSF还具有肿瘤抑制功能。
Correct organ size is determined by the balance between cell death and proliferation. Perturbation of this delicate balance leads to cancer formation. Hippo (Hpo), the Drosophila ortholog of MST1 and MST2 (Mammalian Sterile 20-like 1 and 2) is a key regulator of a signaling pathway that controls both cell death and proliferation. This pathway is so far composed of two Band 4.1 proteins, Expanded (Ex) and Merlin (Mer), two serine/threonine kinases, Hpo and Warts (Wts), the scaffold proteins Salvador (Sav) and Mats, and the transcriptional coactivator Yorkie (Yki). It has been proposed that Ex and Mer act upstream of Hpo, which in turn phosphorylates and activates Wts. Wts phosphorylates Yki and thus inhibits its activity and reduces expression of Yki target genes such as the caspase inhibitor DIAP1 and the micro RNA bantam. However, the mechanisms leading to Hpo activation are still poorly understood. In mammalian cells, members of the Ras association family (RASSF) of tumor suppressors have been shown to bind to MST1 and modulate its activity. In this study, we show that the Drosophila RASSF ortholog (dRASSF) restricts Hpo activity by competing with Sav for binding to Hpo. In addition, we observe that dRASSF also possesses a tumor-suppressor function.
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