FOXK蛋白通过将DVL转运至细胞核来促进Wnt/β-连环蛋白信号传导。
FOXKs promote Wnt/β-catenin signaling by translocating DVL into the nucleus.
作者信息
Wang Wenqi, Li Xu, Lee Moonsup, Jun Sohee, Aziz Kathryn E, Feng Lin, Tran My Kim, Li Nan, McCrea Pierre D, Park Jae-Il, Chen Junjie
机构信息
Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
Department of Genetics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
出版信息
Dev Cell. 2015 Mar 23;32(6):707-18. doi: 10.1016/j.devcel.2015.01.031.
Dishevelled (DVL) proteins serve as crucial regulators that transduce canonical Wnt signals to the GSK3β-destruction complex, resulting in the stabilization of β-catenin. Emerging evidence underscores the nuclear functions of DVLs, which are critical for Wnt/β-catenin signaling. However, the mechanism underlying DVL nuclear localization remains poorly understood. Here we discovered two Forkhead box (FOX) transcription factors, FOXK1 and FOXK2, as bona fide DVL-interacting proteins. FOXK1 and FOXK2 positively regulate Wnt/β-catenin signaling by translocating DVL into the nucleus. Moreover, FOXK1 and FOXK2 protein levels are elevated in human colorectal cancers and correlate with DVL nuclear localization. Conditional expression of Foxk2 in mice induced intestinal hyper-proliferation that featured enhanced DVL nuclear localization and upregulated Wnt/β-catenin signaling. Together, our results not only reveal a mechanism by which DVL is translocated into the nucleus but also suggest unexpected roles of FOXK1 and FOXK2 in regulating Wnt/β-catenin signaling.
蓬乱蛋白（DVL）作为关键调节因子，将经典Wnt信号转导至GSK3β破坏复合物，从而导致β-连环蛋白的稳定。新出现的证据强调了DVL的核功能，这对Wnt/β-连环蛋白信号传导至关重要。然而，DVL核定位的潜在机制仍知之甚少。在这里，我们发现了两个叉头框（FOX）转录因子FOXK1和FOXK2，它们是真正与DVL相互作用的蛋白。FOXK1和FOXK2通过将DVL转运到细胞核中来正向调节Wnt/β-连环蛋白信号传导。此外，FOXK1和FOXK2蛋白水平在人类结直肠癌中升高，并且与DVL核定位相关。在小鼠中条件性表达Foxk2会诱导肠道过度增殖，其特征是DVL核定位增强和Wnt/β-连环蛋白信号传导上调。总之，我们的结果不仅揭示了DVL转运到细胞核的机制，还表明了FOXK1和FOXK2在调节Wnt/β-连环蛋白信号传导中的意外作用。
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