The TEAD/TEF Family Protein Scalloped Mediates Transcriptional Output of the Hippo Growth-Regulatory Pathway

Abstract

The Hippo (Hpo) kinase cascade restricts tissue growth by inactivating the transcriptional coactivator Yorkie (Yki), which regulates the expression of target genes such as the cell death inhibitor diap1 by unknown mechanisms. Here we identify the TEAD/TEF family protein Scalloped (Sd) as a DNA-binding transcription factor that partners with Yki to mediate the transcriptional output of the Hpo growth-regulatory pathway. The diap1 (th) locus harbors a minimal Sd-binding Hpo Responsive Element (HRE) that mediates transcriptional regulation by the Hpo pathway. Sd binds directly to Yki, and a Yki missense mutation that abrogates Sd-Yki binding also inactivates Yki function in vivo. We further demonstrate that sd is required for yki-induced tissue overgrowth and target gene expression, and that sd activity is conserved in its mammalian homolog. Our results uncover a heretofore missing link in the Hpo signaling pathway and provide a glimpse of the molecular events on a Hpo-responsive enhancer element.

The Hippo pathway regulates stem cell proliferation, self-renewal, and differentiation

“…Subsequent biochemical studies showed that Wts directly phosphorylates and inhibits Yki (Dong et al, 2007). Scalloped (Sd), the homolog of mammalian TEAD family transcription factors, were found to be critical partners of Yki in the regulation of gene expression (Goulev et al, 2008;Wu et al, 2008;Zhang et al, 2008;Zhao et al, 2008;Zhang et al, 2009a). Several transcriptional targets of the Hippo pathway have been identified, including cyclin E, which directly promotes cell cycle progression and cell proliferation, and diap1, which inhibits apoptosis (Tapon et al, 2002;Jia et al, 2003;Udan et al, 2003;Wu et al, 2003;Lai et al, 2005).…”

“…The TEAD family transcription factors were identified to be critical partners of YAP and TAZ in the regulation of gene expression (Goulev et al, 2008;Wu et al, 2008;Zhang et al, 2008;Zhao et al, 2008;Zhang et al, 2009a). Disruption of YAP-TEAD interaction abolishes YAP-dependent gene transcription and largely diminishes YAP-induced cell proliferation, oncogenic transformation, and epithelial-to-mesenchymal transition (EMT) .…”

When pathways collide: collaboration and connivance among signalling proteins in development

“…The phosphorylation of Yki by Wts inhibits Yki nuclear localization, preventing it from acting on its growth-promoting and apoptosisinhibiting targets. Yorkie functions with the transcription factor Scalloped in the regulation of growth control [58][59][60] .…”

Regulation of leg size and shape: Involvement of the Dachsous‐fat signaling pathway

“…These proteins suppress growth by the phosphorylation or cytosolic retention of the transcriptional coactivator Yorkie (Yki), which cannot bind to DNA directly (Huang et al, 2005). Yki interacts with a transcription factor Scalloped (Sd), which induces tissue overgrowth (Goulev et al, 2008;Wu et al, 2008;Zhang et al, 2008). The Wts-Hpo signaling factors are now considered as general regulators of organ size in both Drosophila and mammals (Reddy and Irvine, 2008;Halder and Johnson, 2010;Pan, 2010;Zhao et al, 2010).…”