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First published online August 12, 2008
doi: 10.1242/10.1242/dev.020974

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

Howard Hughes Medical Institute, Waksman Institute and Department of Molecular Biology and Biochemistry, Rutgers The State University of New Jersey, Piscataway, NJ 08854, USA.

View larger version (8K): [in this window] [in a new window]   Fig. 1. The Fat-Warts signaling network. A regulatory network perspective of Fat-Warts signaling. Fat PCP signaling is indicated in green, Warts signaling pathways in red. Drosophila gene names are used, except for CD44 and Taz, which are only found in vertebrates. Regulatory inputs include Ds, a ligand for Fat, and hyaluraonate (HA), a ligand for CD44, but other regulators for Expanded and Merlin (?) remain to be identified. Pointed arrows indicate positive effects, block arrows indicate inhibitory effects. As discussed in the text, Warts is likely to have as yet unidentified substrates (?) involved in cell division. Abbreviations: Atro, Atrophin; Ds, Dachsous; Dco, Discs overgrown; Fj, four jointed; Mats, Mob-as-tumor suppressor; Taz, transcriptional co-activator with PDZ-binding motif; Yki, Yorkie.

View larger version (10K): [in this window] [in a new window]   Fig. 2. The Hippo kinase cassette. A schematic of the physical associations and the kinase-substrate relationships among proteins in the Hippo (Hpo) kinase cassette in (A) Drosophila and (B) mammals. Colored arrows identify proteins phosphorylated by Hpo/Mst (blue) and Warts/Lats (green). Hpo and Mst autophosphorylate and then phosphorylate Sav/WW45, Warts/Lats and Mats/Mob. The phosphorylation of Warts by Hpo is facilitated by Sav, which interacts with both proteins. Warts autophosphorylates and phosphorylates downstream effectors, including Yki/Yap, Taz and presumably other substrates (?). Abbreviations: Hpo, Hippo; Mats, Mob-as-tumor suppressor; Sav, Salvador; Taz, transcriptional co-activator with PDZ-binding motif; Yap, Yes-associated protein; Yki, Yorkie.

View larger version (14K): [in this window] [in a new window]   Fig. 3. Transcriptional regulation by Yki and Sd. In Drosophila, Yorkie (Yki) and Scalloped (Sd) form a heterodimeric transcription factor that regulates downstream targets of Warts signaling. Their mammalian homologues Yap and Tead/Tef1-Tef4 (not shown) perform a similar function in mammalian cells. Genetic studies in Drosophila indicate that yki mutation reduces organ growth, whereas sd mutation has little effect outside of the wing. Two possible explanations (which are not mutually exclusive) for this are proposed. (A) In the absence of Yki, target genes might be actively repressed by Sd (right image), presumably in concert with, as yet, unidentified repressors (Rep). Target genes would be expressed at modest levels (thin red line) in the absence of Sd (owing to derepression), but would not to be expressed at all in the absence of Yki. (B) Alternatively, Yki might complex with other DNA-binding proteins (X). These other complexes could then act independently of Sd to promote the expression of the same downstream target genes. In this case, partial expression of targets would occur in the absence of Sd, but not in the absence of Yki.

View larger version (32K): [in this window] [in a new window]   Fig. 4. Warts signaling pathways. A cellular perspective of Warts signaling pathways. (A) In the Warts `on' (phosphorylated) state, Dachs is inhibited by Fat and not detected at the plasma membrane, and does not decrease Warts levels. Discs overgrown (Dco) promotes Fat signaling upstream of Dachs, through an undetermined mechanism. Expanded accumulates at the membrane, and Expanded and Merlin are activated by unknown regulators, and, in mammalian cells, by CD44. Expanded and Merlin promote Hpo phosphorylation (P), which in turn promotes phosphorylation of Salvador (Sav), Warts and Mob-as-tumor suppressor (Mats), contributing to the assembly of these proteins into complexes. Active Warts phosphorylates Yorkie (Yki), which inhibits Yki by promoting its association with 14-3-3 proteins in the cytoplasm, thereby excluding it from the nucleus. (B) In the Warts `off' (unphosphorylated) state, Dachs accumulates at the membrane, reduces levels of Warts protein and reduces levels of Ex protein at the membrane. Merlin is in its inactive, phosphorylated, state. Components of the Hippo (Hpo) kinase cassette are unphosphorylated, and interactions between them are reduced. Yki is not phosphorylated, and enters the nucleus where it complexes with Scalloped (Sd) to promote the transcription of downstream target genes.

View larger version (24K): [in this window] [in a new window]   Fig. 5. Fj and Ds expression gradients and the regulation of PCP. (A) dachsous (ds) expression, revealed by a ds-lacZ enhancer trap, is graded in the Drosophila eye, with higher levels at the poles (P) and lower levels at the equator (E). (B) four-jointed (fj) expression, revealed by a fj-lacZ enhancer trap, is in a complementary pattern, with levels high at the equator and low at the poles. (C-E) Schematic perspectives of polarity in the eye in different genotypes. Broken lines with arrows indicate vectors of planar cell polarity, which in the eye is manifest in the orientation of ommatidia. Magenta and blue lines represent the Ds and Fj expression gradients, respectively. (C) In wild-type flies, the arrangement of ommatidia is symmetrical with respect to the equator of the eye, represented here by arrows pointing out towards the poles. The vector of polarity can thus be thought of as ascending the Ds slope and descending the Fj slope. (D) In an fj- mutant, the vector of polarity continues to ascend the Ds slope and PCP is essentially normal. (E) In an eye with fj mutant clones (left side) or fj overexpressing clones (right side), reversals of polarity occur where the change in fj expression causes a local reversal of the gradient (Zeidler et al., 1999).

View larger version (22K): [in this window] [in a new window]   Fig. 6. Model for how polarization of Fat activity might influence Warts signaling. A proposed model for how differences in Dachsous (Ds) or Four-jointed (Fj) expression might affect both planar cell polarity (PCP) and Warts signaling pathways (Rogulja et al., 2008). (A) A cell that encounters higher levels of Ds on the cell to its left and lower levels of Ds on the cell to its right. Ds gradients are associated with the polarization of Dachs localization, which is mediated by Fat (Mao et al., 2006). The establishment of polarized protein localizations, including that of Dachs, but presumably also of other proteins, may initiate the cellular polarization associated with PCP. Dachs also inhibits Warts. In the model, this occurs locally, such that when Dachs is polarized, Warts could be degraded and rendered inactive (colorless oval) on one side of a cell (right, in this case), but abundant and active (colored oval) on the other side. Where Warts is present and active, it would phosphorylate and inhibit Yorkie (Yki), but where Warts is missing or inactive, Yki would not be phosphorylated and hence could enter the nucleus. (B) A cell that encounters higher levels of Fj expressed in the cell to its left and lower levels of Fj expressed in the cell to its right. The opposing influences of Fj and Ds on PCP and Dachs localization suggest that this is functionally equivalent to a situation in which Ds levels are higher in the cell to the right and lower in the cell to the left. This polarizes the cell in the opposite direction, such that Dachs now accumulates on the membrane on the left side of the cell, rather than on the right side. Even though the cell is polarized in the opposite direction, the transcriptional response associated with failure to locally phosphorylate Yki could be the same for A and B.

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