Article

Mask Proteins Are Cofactors of Yorkie/YAP in the Hippo Pathway

Cancer Research UK, London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
Current biology: CB (Impact Factor: 9.92). 01/2013; 23(3). DOI: 10.1016/j.cub.2012.11.061
Source: PubMed

ABSTRACT The Hippo signaling pathway acts via the Yorkie (Yki)/Yes-associated protein (YAP) transcriptional coactivator family to control tissue growth in both Drosophila and mammals [1-3]. Yki/YAP drives tissue growth by activating target gene transcription, but how it does so remains unclear. Here we identify Mask as a novel cofactor for Yki/YAP. We show that Drosophila Mask forms a complex with Yki and its binding partner, Scalloped (Sd), on target-gene promoters and is essential for Yki to drive transcription of target genes and tissue growth. Furthermore, the stability and subcellular localization of both Mask and Yki is coregulated in response to various stimuli. Finally, Mask proteins are functionally conserved between Drosophila and humans and are coexpressed with YAP in a wide variety of human stem/progenitor cells and tumors.

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    • "The fly stocks used were dac 3 , UAS - dac F ( Mardon et al . , 1994 ) , UAS - HA : dac F ( Tavsanli et al . , 2004 ) , eya E8 ( Bonini et al . , 1998 ) , tkv 4 , hpo 42 – 47 ( Wu et al . , 2003b ) , UAS - hth - GFP ( Casares and Mann , 2000 ) , UAS - yki ( Huang et al . , 2005 ) , UAS - yki : HA ( Sidor et al . , 2013 ) , UAS - yki - IR 4005R - 2 ( NIG ) , UAS - hth - IR ( VDRC #12763 ) , UAS - ex ( Udan et al . , 2003 ) , GFP - ban sensor ( Brennecke et al . , 2003 ) , ban - lacZ ( Spradling et al . , 1999 ) , UAS - ban EP ( 3 ) 3622 ( Rorth et al . , 1998 ) , UAS - ban - sponge ( Becam et al . , 2011 ) , Diap1 : : lacZ ( Hay et al . , 1995 ) , ptc "
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    ABSTRACT: The Drosophila transcriptional co-activator protein Yorkie and its vertebrate orthologs YAP and TAZ are potent oncogenes, whose activity is normally kept in check by the upstream Hippo kinase module. Upon its translocation into the nucleus, Yorkie forms complexes with several tissue-specific DNA-binding partners, which help to define the tissue-specific target genes of Yorkie. In the progenitor cells of the eye imaginal disc, the DNA-binding transcription factor Homothorax is required for Yorkie-promoted proliferation and survival through regulation of the bantam microRNA (miRNA). The transit from proliferating progenitors to cell cycle quiescent precursors is associated with the progressive loss of Homothorax and gain of Dachshund, a nuclear protein related to the Sno/Ski family of co-repressors. We have identified Dachshund as an inhibitor of Homothorax-Yorkie-mediated cell proliferation. Loss of dachshund induces Yorkie-dependent tissue overgrowth. Conversely, overexpressing dachshund inhibits tissue growth, prevents Yorkie or Homothorax-mediated cell proliferation of disc epithelia and restricts the transcriptional activity of the Yorkie-Homothorax complex on the bantam enhancer in Drosophila cells. In addition, Dachshund collaborates with the Decapentaplegic receptor Thickveins to repress Homothorax and Cyclin B expression in quiescent precursors. The antagonistic roles of Homothorax and Dachshund in Yorkie activity, together with their mutual repression, ensure that progenitor and precursor cells are under distinct proliferation regimes. Based on the crucial role of the human dachshund homolog DACH1 in tumorigenesis, our work suggests that DACH1 might prevent cellular transformation by limiting the oncogenic activity of YAP and/or TAZ. © 2015. Published by The Company of Biologists Ltd.
    Development 03/2015; 142(8). DOI:10.1242/dev.113340 · 6.27 Impact Factor
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    • "The overexpression of ANKHD1 has been reported in acute leukemias [15] and multiple myeloma cells [16], and has been found to be associated with a significantly decreased survival in breast cancer patients [17]. The recent identification of ANKHD1 as a novel member of the Hippo signaling pathway has provided new possibilities for investigation [17] [18]. "
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    ABSTRACT: ANKHD1 is a multiple ankyrin repeat containing protein, recently identified as a novel member of the Hippo signaling pathway. The present study aimed to investigate the role of ANKHD1 in DU145 and LNCaP prostate cancer cells. ANKHD1 and YAP1 were found to be highly expressed in prostate cancer cells, and ANKHD1 silencing decreased cell growth, delayed cell cycle progression at the S phase, and reduced tumor xenograft growth. Moreover, ANKHD1 knockdown downregulated YAP1 expression and activation, and reduced the expression of CCNA2, a YAP1 target gene. These findings indicate that ANKHD1 is a positive regulator of YAP1 and promotes cell growth and cell cycle progression through Cyclin A upregulation.
    Experimental Cell Research 04/2014; 324(2). DOI:10.1016/j.yexcr.2014.04.004 · 3.37 Impact Factor
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    ABSTRACT: The Drosophila Yorkie (Yki) protein and its mammalian homolog Yes-associated protein (YAP) are potent growth promoters, and YAP overexpression is associated with multiple types of cancer [1, 2]. Yki and YAP are transcriptional coactivators and function as downstream effectors of the Hippo tumor suppressor pathway [1-4]. The regulation of Yki and YAP by the Hippo signaling pathway has been extensively investigated; however, how they regulate gene expression is poorly understood. To identify additional regulators of Yki activity, we performed a genome-wide RNAi screen in Drosophila S2 cells. In this screen, we identified the conserved protein Mask (Multiple ankyrin repeats single KH domain) as a novel promoter of Yki activity in vitro and validated this function in vivo in Drosophila. We found that Mask is required downstream of the Hippo pathway for Yki to induce target-gene expression and that Mask forms complexes with Yki. The human Mask homolog MASK1 complexes with YAP and is required for the full activity of YAP. Additionally, elevated MASK1 expression is associated with worsened outcomes for breast cancer patients. We conclude that Mask is a novel cofactor for Yki/YAP required for optimal Yki/YAP activity during development and oncogenesis.
    Current biology: CB 01/2013; 23(3). DOI:10.1016/j.cub.2012.12.033 · 9.92 Impact Factor
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