The Hippo Signaling Pathway Coordinately Regulates Cell Proliferation and Apoptosis by Inactivating Yorkie, the Drosophila Homolog of YAP

Abstract

Coordination between cell proliferation and cell death is essential to maintain homeostasis in multicellular organisms. In Drosophila, these two processes are regulated by a pathway involving the Ste20-like kinase Hippo (Hpo) and the NDR family kinase Warts (Wts; also called Lats). Hpo phosphorylates and activates Wts, which in turn, through unknown mechanisms, negatively regulates the transcription of cell-cycle and cell-death regulators such as cycE and diap1. Here we identify Yorkie (Yki), the Drosophila ortholog of the mammalian transcriptional coactivator yes-associated protein (YAP), as a missing link between Wts and transcriptional regulation. Yki is required for normal tissue growth and diap1 transcription and is phosphorylated and inactivated by Wts. Overexpression of yki phenocopies loss-of-function mutations of hpo or wts, including elevated transcription of cycE and diap1, increased proliferation, defective apoptosis, and tissue overgrowth. Thus, Yki is a critical target of the Wts/Lats protein kinase and a potential oncogene.

WWC2 is an independent prognostic factor and prevents invasion via Hippo signalling in hepatocellular carcinoma

“…Activated LATS1/2 phosphorylate YAP, which inhibited cell proliferation in mammalian cells 38, 39, 40. In confirmation that WWC2 activates the Hippo pathway in HCC, overexpression of WWC2 in SMMC‐7721 cells (which express low levels of WWC2) increased phosphorylation of both LATS and YAP, which has been previously shown to negatively regulate the Hippo pathway 11, 41, 42. The latter study also revealed HCC cells transfected with the WWC2 overexpression plasmid decreased the mRNA level of Cyr61 and CTGF, both which are the target genes of Hippo pathway.…”

Loss of PI3K blocks cell-cycle progression in a Drosophila tumor model

“…To test whether this is the case, we manipulated other tumor suppressor pathways to generate tissue overgrowths and tested whether these overgrowths were also sensitive to manipulation of the PI3K pathway. Either downregulation of the Hippo tumor suppressor pathway by overexpression of the Yorki (Yki) transcriptional activator or misregulation of the JAK-STAT pathway by overexpression of the Unpaired (Upd) ligand caused overgrown imaginal disc tissues (Bach et al, 2003;Huang et al, 2005). However, compared with the Ras V12 , Dlg RNAi tumors, expression of either Yki or Upd alone resulted in only mildly overgrown discs .…”

Germinal center kinases in immune regulation

“…15 Compared to NOTCH signaling, Hedgehog signaling and Wnt signaling, the relatively novel Hpo pathway is currently undergoing extensive investigation. The core components of Hpo pathway include Hpo, Warts, Sav and Mats, all of which are highly conserved ( Figure 2).…”