Yorkie: the final destination of Hippo signaling

Abstract

The Hippo signaling pathway is a key regulator of growth during animal development, whereas loss of normal Hippo pathway activity is associated with a wide range of cancers. Hippo signaling represses growth by inhibiting the activity of a transcriptional co-activator protein, known as Yorkie in Drosophila and Yap in vertebrates. In the 5 years since the first report linking Yorkie to Hippo signaling, intense interest in this pathway has led to rapid increases in our understanding of the action and regulation of Yorkie/Yap, which we review here. These studies have also emphasized the complexity of Yorkie/Yap regulation, including multiple, distinct mechanisms for repressing its transcriptional activity, and multiple DNA-binding partner proteins that can direct Yorkie to distinct downstream target genes.

Figure I

Linear schematics of Drosophila components of the Hpo pathway

Figure 1. The Hippo signaling pathway

Schematic depictions of the regulatory interactions among genes linked to Hippo signaling. Pointed arrows indicate a positive regulatory connection, blocks indicate an inhibitory regulatory connection. Genes depicted in red can function as tumor suppressors (loss of function mutations can cause overgrowth), genes depicted in green can function as oncogenes (over expression and/or activation can cause overgrowth), genes depicted in black have not been shown to function as tmor suppressors or oncogenes. At the botom, genes depicted in gray encode DNA binding proteins that can partner with Yki/Yap to influence transcription of downstream target genes. Hippo signaling influences growth by influencing the transcription of target genes, but transcriptional targets that are not directly related to growth control have also been identified. A) Depicts genes and regulatory links identified in Drosophila. B) Depicts some of the genes identified in mammals. The Fat regulatory branch is shaded by a grey box to indicate that it is not yet known whether these genes actually influence Hpo signaling in mammals.

Figure 2. Multiple modes of Yki/Yap regulation

This schematic depicts some of the different ways in which Yki/Yap is known to be regulated within the cell, gray oval represents the nucleus. 1) Yki/Yap can be transcriptionally regulated; increased transcription has been implicated in medulloblastoma. 2) Phosphorylation of Yki/Yap by Warts/Lats (green arrows) creates a 14-3-3 binding site, which promotes cytoplasmic localization of Yki/Yap. Wts activity is regulated by Hpo-dependent phosphorylation (blue arrows). 3) Phosphorylation of Yap by Lats makes it a substrate for CKI phosphorylation, which recruits SCF, leading to Yap ubiquitination and degradation (small yellow boxes). 4) Direct binding of Yki to Wts and Ex can retain Yki in the cytoplasm. 5) Yki/Yap can be exported from the nucleus in a CRM1-dependent fashion. 6) Nuclear Yki/Yap can associate with distinct DNA-binding transcription factors to regulate distinct downstream target genes.