Yorkie’s Elusive Partner

Abstract

The Hippo (Hpo) kinase cascade plays a critical role, conserved from Drosophila to mammals, in the control of cell proliferation and organ size. As a consequence of Hpo activation in Drosophila , the transcriptional coactivator Yorkie (Yki) is phosphorylated and sequestered in the cytoplasm. The exclusion of Yki from the nucleus results in the reduced expression of cyclin E , which stimulates cell proliferation, and diap1 , which is an antiapoptotic gene. Two aspects of Hpo signaling that have thus far remained elusive are the identity of the transcription factor that pairs with Yki to stimulate cell growth and whether Yki directly activates the genes whose expression is antagonized by Hpo. Two groups, Zhang et al . and Wu et al ., performed very similar studies that identified the transcription factor Scalloped (Sd), a homolog of mammalian TEF proteins, as the binding partner of Yki. Reporter assays in a Drosophila cell line showed that the Sd-Yki complex formed a transcriptional unit whose activity was inhibited by Hpo. In Drosophila , outgrowth of cells in the eye caused by the overexpression of Yki was blocked when Sd was depleted by RNA interference, as was Yki-mediated expression of Hpo-target genes. Binding of Sd to Yki was necessary for both the nuclear translocation of Yki and the recruitment of Yki to the diap1 enhancer, the first evidence of the direct activation of an Hpo-target gene by Yki. Considering that the mammalian Yki homolog YAP is implicated in organ outgrowth and certain cancers (see Bandura and Edgar), these studies suggest that TEF-YAP complexes, the mammalian homologs of Sd-Yki, may serve as targets for therapies against tumorigenesis. L. Zhang, F. Ren, Q. Zhang, Y. Chen, B. Wang, J. Jiang, The TEAD/TEF family of transcription factor Scalloped mediates Hippo signaling in organ size control. Dev . Cell 14 , 377-387 (2008). [PubMed] S. Wu, Y. Liu, Y. Zheng, J. Dong, D. Pan, The TEAD/TEF family protein Scalloped mediates transcriptional output of the Hippo growth-regulatory pathway. Dev . Cell 14 , 388-398 (2008). [PubMed] J. L. Bandura, B. A. Edgar, Yorkie and Scalloped: Partners in growth activation. Dev . Cell 14 , 315-316 (2008). [PubMed]