Models of the Hippo pathway in Drosophila and mammals

Models of the Hippo pathway in Drosophila and mammals. In Drosophila, Fat protocadherin may initiate the Hippo pathway signal in response to Ds binding, and is modulated by binding of Lft and phosphorylation by Dco (; ; ). Fat may inhibit a nonconventional myosin Dachs, which represses Wts protein levels (). Fat may also activate Ex with an unknown mechanism (; ; ; ). Mer and Ex also activate the Hippo pathway (). They may form a complex with Hpo and Sav (). Kibra interacts with both Mer and Ex, and may also be in the complex (). Hpo kinase interacts with and phosphorylates a scaffold protein, Sav (). Together, they phosphorylate and activate Wts kinase and its associated protein, Mats (). Wts phosphorylates a transcription coactivator, Yki, on three sites (). Phosphorylation of Yki S168 induces 14–3–3 binding and cytoplasmic retention (). Yki may also be retained in the cytoplasm by physical interaction with Ex, Wts, and Hpo (; ). When Yki is relieved from inhibition and gets into the nucleus, it binds and activates a transcription factor, Sd, to induce cycE, diap1, and ex expression (; ; ). Yki induces bantam microRNA through Hth and Tsh (). In mammals, functional significance of Fat and Ex homologs are not clear. However, Mer may still activate the Hippo pathway (). RASSF, a subgroup of Ras effector proteins, may also activate Mst1/2 (Hpo homolog) (). Relationships between Hpo, Sav, Wts, and Mats are basically conserved in mammalian Mst1/2, Sav1 (Sav homolog), Lats1/2 (Wts homolog), and Mob (Mats homolog). Lats1/2 phosphorylates YAP on five conserved HXRXXS motifs (four on TAZ) (). Dependent on cell context, there may exist another YAP kinase in response to Mst1/2 and another Lats1/2 kinase (). S127 (S89 in TAZ) phosphorylation-dependent 14–3–3 binding and cytoplasmic retention are conserved in YAP/TAZ (; ). YAP is also inhibited by S381 phosphorylation, which primes CK1δ/ɛ phosphorylation of S384, and S387 finally leads to SCFβ-TRCP-mediated ubiquitination and degradation (). Sd homologs, TEADs, are major YAP target transcription factors. They mediate expression of CTGF, Gli2, and many other target genes (). AREG is induced by YAP through an unidentified transcription factor (). YAP and TAZ also bind Smad1 and Smad2/3 to activate expression of TGF-β and BMP target genes, respectively, to maintain stem cell pluripotency (; ).

Publication

The Hippo–YAP pathway in organ size control and tumorigenesis: an updated version. (2010) Bin Zhao, et al. Genes Dev. 2010 May 1;24(9):862-874. Figure: F2. All organisms Drosophila melanogaster Homo sapiens

Disease mentions