Ras-activated Dsor1 promotes Wnt signaling in Drosophila development
Ras-activated Dsor1 promotes Wnt signaling in Drosophila development
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DOI：
10.1242/jcs.175240
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发表时间：
2015-12-15
影响因子：
4
通讯作者：
Verheyen, Esther M.
中科院分区：
文献类型：
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作者：
Hall, Eric T.;Verheyen, Esther M.
WNT/Wingless(Wg)和Ras-MAPK信号在生长和细胞命运决定中都发挥着基础作用，当调控失调时，可以导致肿瘤的发生。在特定的细胞环境中，Ras-MAPK和Wnt信号之间的几种相互冲突的相互作用模式已经被发现，从而对靶基因产生协同或拮抗效应。我们发现新的证据表明，Raf1(Dsor1)下游的双特异性激酶MEK1/2(也称为MAP2K1/2)的果蝇同源物是Wnt信号所必需的。Dsor1的敲除会导致Wg靶基因表达的丧失，以及稳定的Armadillo(ARM；果蝇β-连环蛋白)的减少。我们发现Dsor1和ARM之间存在密切的物理相互作用，并发现催化不活跃的Dsor1会导致活性ARM的减少。这些结果表明，Dsor1正常情况下可以抵消Axin介导的ARM破坏。我们发现Ras-Dsor1的活性不依赖于EGFR的上游激活，而似乎是被胰岛素样生长因子受体激活以促进Wg信号转导。综上所述，我们的结果表明，在胰岛素和Wg信号之间存在一条新的由Dsor1介导的串扰通路。
Wnt/Wingless (Wg) and Ras-MAPK signaling both play fundamental roles in growth and cell fate determination, and when dysregulated, can lead to tumorigenesis. Several conflicting modes of interaction between Ras-MAPK and Wnt signaling have been identified in specific cellular contexts, causing synergistic or antagonistic effects on target genes. We find novel evidence that the Drosophila homolog of the dual specificity kinases MEK1/2 (also known as MAP2K1/2), Downstream of Raf1 (Dsor1), is required for Wnt signaling. Knockdown of Dsor1 results in loss of Wg target gene expression, as well as reductions in stabilized Armadillo (Arm; Drosophila beta-catenin). We identify a close physical interaction between Dsor1 and Arm, and find that catalytically inactive Dsor1 causes a reduction in active Arm. These results suggest that Dsor1 normally counteracts the Axin-mediated destruction of Arm. We find that Ras-Dsor1 activity is independent of upstream activation by EGFR, and instead it appears to be activated by the insulin-like growth factor receptor to promote Wg signaling. Taken together, our results suggest that there is a new crosstalk pathway between insulin and Wg signaling that is mediated by Dsor1.