The Hippo Signaling Pathway in Development and Cancer

Abstract

First discovered in Drosophila, the Hippo signaling pathway is a conserved regulator of organ size. Central to this pathway is a kinase cascade leading from the tumor suppressor Hippo (Mst1 and Mst2 in mammals) to the oncoprotein Yki (YAP and TAZ in mammals), a transcriptional coactivator of target genes involved in cell proliferation and survival. Here, I review recent progress in elucidating the molecular mechanism and physiological function of Hippo signaling in Drosophila and mammals. These studies suggest that the core Hippo kinase cascade integrates multiple upstream inputs, enabling dynamic regulation of tissue homeostasis in animal development and physiology.

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

“…The Ds-Ft signaling pathway may regulate leg size through the Wts signaling pathway, as shown in Figure 7 ( Bando et al, 2009). This is consistent with the observation that the WtsHpo signaling pathway is involved in an intrinsic mechanism that restricts organ size (Edgar, 2006;Dong et al, 2007;Pan, 2007Pan, , 2010Yin and Pan, 2007;Lawrence et al, 2008;Zhao et al, 2010). Thus, when neighboring cells express different amounts of Ds or Ft during regeneration (Fig.…”

“…This function has been linked to the WtsHpo signaling pathway (Fig. 1C) (Huang et al, 2005;Cho et al, 2006;Edgar, 2006;Reddy and Irvine, 2008;Pan, 2010), including Lowfat (Lft), Warts (Wts), Hpo kinases, Salvador, Mob-as-tumor-suppressor, and the 4.1, ezrin, radixin, moesin (FERM) domain proteins Expanded (Ex), Merlin (Mer), and Kibra ( Fig. 1C) (for a recent review, see Halder and Johnson, 2010).…”

“…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). Thus, it is reasonable to speculate that the DsFt and Wts-Hpo signaling pathways are involved in controlling the size of various organs.…”

“…Since several excellent reviews have been published on these signaling pathways (for recent reviews, see Kango-Singh and Singh, 2009;L. Zhang et al, 2009;Grusche et al, 2010;Halder and Johnson, 2010;Oh and Irvine, 2010;Pan, 2010;Yi and Kissil, 2010;Zhao et al, 2010), we have not described these pathways in detail in this review. Rather, we aim to review recent advances in determining leg segment size and PVs in the leg segment, focusing on the Ds-Ft and Wts-Hpo signaling pathways.…”

“…Yellow indicates factors whose RNAi phenotypes were observed during Gryllus leg regeneration (Bando et al, 2009). D: Gene names and symbols are as follows; 14-3-3e (14-3-3e), 14-3-3j (14-3-3j), Approximated (App), Cyclin B (CycB), Cyclin E (CycE), Dachs (D), Discs overgrown (Dco), Drosophila inhibitor of apoptosis 1 (Diap1), Dachsous (Ds), Expanded (Ex), Fat (Ft), Four-jointed (Fj), Grunge (Gug), Hippo (Hpo), Kibra (Kibra), Lowfat (Lft), Mob as tumor suppressor (Mats), Merlin (Mer), Ras association family (Rassf), Salvador (Sav), Scalopped (Sd), Serrate (Ser), Warts (Wts), Yorkie (Yki) (Varelas et al;Bando et al, 2009;Grusche et al, 2010;Kim et al 2010;Pan, 2010;Zhao et al, 2010).…”