The Fat and Warts signaling pathways: new insights into their regulation,mechanism and conservation

Abstract

A cassette of cytoplasmic Drosophila tumor suppressors, including the kinases Hippo and Warts, has recently been linked to the transmembrane tumor suppressor Fat. These proteins act within interconnected signaling pathways, the principal functions of which are to control the growth and polarity of developing tissues. Recent studies have enhanced our understanding of the basis for signal transduction by Fat and Warts pathways, including the identification of a DNA-binding protein at the end of the pathway, have established the conservation of Fat and Warts signaling from flies to mammals,and have given us new insights into their regulation and biological functions.

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

“…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.…”

“…In the wing disc, ds is highly expressed in proximal regions, and fj is expressed distally, whereas ft is expressed uniformly throughout the disc (Fig. 4) (Garoia et al, 2000;Mao et al, 2006;Reddy and Irvine, 2008). Since uniform misexpression of Fj and Ds in the wing disc inhibits cell proliferation and growth, graded expression of Ft regulators such as Fj and Ds could modulate Ft signaling by polarizing Ft activity within the cell (Rogulja et al, 2008;Willecke et al, 2008).…”

“…Using the rdRNAi method, Bando et al (2009) examined the function of genes involved in the Ds-Ft signaling pathway. On the basis of the data in Drosophila (Reddy and Irvine, 2008), they selected a set of 23 genes in the Ds-Ft signaling pathway (Fig. 1C) and found at least 15 genes are involved in leg regeneration, indicated by yellow in Figure 1C (Bando et al, 2009).…”

Stem cells in liver regeneration, fibrosis and cancer: the good, the bad and the ugly

“…On the other hand, over-expression of the Yes-associated protein (YAP) in a conditional YAP transgenic mouse led to a phenomenal liver weight increase through hyperplasia, reaching 25% of body weight -normal liver weight is ∼5% of body weight [16]. YAP transcriptionally activates cell cycle proteins such as Ki-67 and c-Myc and also inhibitors of apoptosis, and its phosphorylation by way of activation of the 'Hippo' pathway blocks its ability to shuttle to the nucleus [17]. The Hippo pathway is considered to be a 'size checkpoint' operating at the level of the organ's total mass, perhaps reminiscent of the 'chalone' hypothesis that was fashionable in the 1970s, which held that the size of each organ was controlled by a tissue-specific chalone, produced by differentiated cells, that negatively regulated the progenitor compartment [18,19].…”