| |||
|
|
|||
|
      |
|
 |
|
| |||||||||||
| |||||||||||
| |||||||||||
| | | | ||||||||
| Cell proliferation and apoptosis: Merlin works its magic on Hippo
The tumor suppressors Merlin and Expanded regulate tissue growth in Drosophila upstream of Hippo. Some genes that control tissue growth through the inhibition of cell proliferation and promotion of apoptosis, are not only important for normal development, but also prevent tumor growth in adults. A new study published in Nature Cell Biology shows that Neurofibromatosis type-2/Merlin (Mer), a well established tumor suppressor in vertebrates, signals through Hippo (Hpo) to regulate tissue growth in developing flies.
The highly conserved serine/threonine kinase Hpo regulates the expression of genes involved in tissue growth by phosphorylating Warts (Wts), which in turn inhibits the transcriptional activator Yorkie (Yki). The mammalian homologues of Hpo and Wts, Mst(1/2) and Lats1/2 respectively, have also been implicated in the regulation of cell growth and apoptosis. Similarly, Mer has been shown to function together with another FERM domain-containing protein, Expanded (Ex), through an unknown signaling pathway, to regulate cell proliferation. Hamaratoglu et al. now report that mer;ex double-mutants exhibit a similar tissue overgrowth phenotype in developing retinas to that observed in Hpo mutants. Mutation of either Hpo or mer and ex causes overproliferation of interommatidial pigment cells as a result of increased cell proliferation and defective apoptosis. The fact that Mer and Ex are able to induce Wts phosphorylation and suppress Yki activity, and that the same target genes (Cyclin E and Drosophila Inhibitor of Apoptosis Protein-1) are upregulated in Hpo and mer;ex mutants, suggests that Hpo, Mer and Ex function in the same signaling pathway. Epistatic analyses demonstrate the Mer and Ex act upstream of Hpo. Overexpression of both Hpo and Ex leads to a loss of interommatidial pigment cells, but whilst Ex and Mer mutations do not suppress the Hpo overexpression phenotype, loss of Hpo function suppresses the effect of Ex overexpression. The authors also identify Mer and Ex as targets of Hpo signaling, thereby uncovering a negative feedback mechanism. In agreement with their previous findings, they show that hyperactivation of Hpo is sufficient to rescue the upregulation of Ex observed in ex mutant cells. Due to the high degree of Hpo signaling pathway component conservation between flies and mice, these results could shed light on the mechanism through which Mer exerts its tumor suppressor function in vertebrates. Monica Hoyos-Flight
References
| |
| ||||||||
| |||||||||||
 | |||||||||||
| |||||||||||
| |||||||||||
| |||||||||||
HOME | SIGNALING UPDATE | MOLECULE PAGES | DATA CENTER | ABOUT US | |||||||||||
| |||||||||||
