IMP3 Stabilization of WNT5B mRNA Facilitates TAZ Activation in Breast Cancer

Publication date: 29 May 2018
Source:Cell Reports, Volume 23, Issue 9
Author(s): Sanjoy Samanta, Santosh Guru, Ameer L. Elaimy, John J. Amante, Jianhong Ou, Jun Yu, Lihua J. Zhu, Arthur M. Mercurio
Insulin-like growth factor-2 mRNA-binding protein 3 (IMP3) is an oncofetal protein associated with many aggressive cancers and implicated in the function of breast cancer stem cells (CSCs). The mechanisms involved, however, are poorly understood. We observed that IMP3 facilitates the activation of TAZ, a transcriptional co-activator of Hippo signaling that is necessary for the function of breast CSCs. The mechanism by which IMP3 activates TAZ involves both mRNA stability and transcriptional regulation. IMP3 stabilizes the mRNA of an alternative WNT ligand (WNT5B) indirectly by repressing miR145-5p, which targets WNT5B, resulting in TAZ activation by alternative WNT signaling. IMP3 also facilitates the transcription of SLUG, which is necessary for TAZ nuclear localization and activation, by a mechanism that is also mediated by WNT5B. These results demonstrate that TAZ can be regulated by an mRNA-binding protein and that this regulation involves the integration of Hippo and alternative WNT-signaling pathways.

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Teaser

Mechanisms that regulate TAZ are critical for understanding the biology and improving the therapy of breast and other cancers. Samanta et al. demonstrate that insulin-like growth factor-2 mRNA-binding protein 3 (IMP3) contributes to TAZ activation in breast cancer stem cells by stabilizing WNT5B mRNA and facilitating alternative Wnt signaling. IMP3 and WNT5B also function together to promote the transcription of SLUG, which is necessary for TAZ nuclear localization and activation.


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