Editors' ChoiceDevelopmental Biology

Yorkie’s Mask

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Science Signaling  12 Feb 2013:
Vol. 6, Issue 262, pp. ec38
DOI: 10.1126/scisignal.2004053

Signaling through the Hippo pathway suppresses cell growth by inhibiting the nuclear localization and activity of the transcriptional coactivator Yorkie (Yki) in the fly and its mammalian homolog Yes-associated protein (YAP). In conjunction with transcription factors such as Scalloped (Sd), Yki promotes growth by activating the expression of genes that drive cell proliferation and survival, but details of the mechanisms by which Yki activates gene transcription are incomplete. Two reports identify multiple ankyrin repeats single KH domain (Mask) as a cofactor for Yki in the fruit fly Drosophila melanogaster. Sidor et al. and Sansores-Garcia et al. identified mask in RNA interference (RNAi)–based screens for genes that contribute to tissue growth in Drosophila and cooperate with Yki to drive expression of a Yki-responsive luciferase reporter in cultured fly S2 cells, respectively. Like yki mutant clones, mask null clones in larval eye and wing discs grew poorly compared with heterozygous cells, resulting in adult structures that were smaller than wild type. Mask was required for Yki to exert its growth-promoting effects in the wing, and RNAi-mediated knockdown or mutation of mask reduced the activation of Yki-dependent target genes in wing discs. Moreover, mutation of mask suppressed the activation of Yki target genes induced by mutation of the gene that encodes Warts (Wts), a kinase that phosphorylates Yki to inhibit its activity in response to Hippo signaling. Mask was not required for Yki to enter the nucleus in wing disc or S2 cells and was not absolutely required for all Yki activity, because expression of Yki-responsive genes was not completely lost in the absence of Mask. Sansores-Garcia et al. coimmunoprecipitated tagged Yki and Mask proteins from S2 cell lysates, and Sidor et al. showed that endogenous Mask and transgenically expressed Yki and Sd were present on the promoter of an endogenous Yki-responsive gene in S2 cells. Sansores-Garcia et al. coimmunoprecipitated endogenous human MASK1 with endogenous YAP and the Sd homolog TEAD3 from human embryonic kidney (HEK) 293T cell lysates, and both groups detected endogenous MASK1-YAP complexes in the cytoplasm and nuclei of HEK293T cells. Sansores-Garcia et al. demonstrated that MASK1 was required for maximal expression of YAP target genes. Decreased Hippo signaling and increased YAP activity correlate with poor prognosis in various human cancers, and meta-analysis of breast cancer microarray data by Sansores-Garcia et al. showed that low expression of MASK1 correlated with better prognosis. Identification of this additional player that promotes Yki activity independently of Wts adds another layer of complexity to this important growth-regulating pathway.

C. M. Sidor, R. Brain, B. J. Thompson, Mask proteins are cofactors of Yorkie/YAP in the Hippo pathway. Curr. Biol. 23, 223–228 (2013). [PubMed]

L. Sansores-Garcia, M. Atkins, I. M. Moya, M. Shahmoradgoli, C. Tao, G. B. Mills, G. Halder, Mask is required for the activity of the Hippo pathway effector Yki/YAP. Curr Biol. 23, 229–235 (2013). [PubMed]

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