FOXKs promote Wnt/β-catenin signaling by translocating DVL into the nucleus

Dev Cell. 2015 Mar 23;32(6):707-18. doi: 10.1016/j.devcel.2015.01.031.

Wenqi Wang ¹, Xu Li ¹, Moonsup Lee ², Sohee Jun ¹, Kathryn E Aziz ¹, Lin Feng ¹, My Kim Tran ¹, Nan Li ¹, Pierre D McCrea ², Jae-Il Park ¹, Junjie Chen ³

Affiliations

1 Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
2 Department of Genetics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
3 Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA. Electronic address: [email protected].

PMID: 25805136 DOI: 10.1016/j.devcel.2015.01.031

Abstract

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.

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