The Salvador–Warts–Hippo pathway — an emerging tumour-suppressor network

Key Points

  • The Salvador–Warts–Hippo (SWH) pathway controls organ size by modulating cell growth, proliferation and apoptosis.

  • Deregulation of this pathway in Drosophila melanogaster leads to dramatic increases in organ size.

  • Proteins predicted to function in the SWH pathway include the cadherin Fat, the band 4.1 proteins Expanded and Merlin, the kinases Hippo, Warts and Discs overgrown, the adaptor molecules Salvador, Mats and Dachs, dRASSF and the transcriptional co-activator Yorkie.

  • SWH pathway components are conserved throughout evolution from yeast to humans, and the pathway has been implicated in the genesis of human cancers.

  • The human orthologue of merlin (NF2) is a bona fide tumour-suppressor gene, which is mutated in the familial cancer syndrome neurofibromatosis type 2. Homologues of warts, salvador, mats (mob as tumour suppressor), dRASSF (Ras association family) and yorkie have also been implicated in mammalian tumorigenesis.

  • Important target genes of the SWH pathway include cyclin E (which drives cell proliferation), DIAP1 (which inhibits apoptosis) and the bantam microRNA. The pathway also controls expanded and four-jointed expression in apparent regulatory feedback loops.

  • Potential regulatory processes that control SWH pathway activity include the modification of expression and sub-cellular localization of Expanded, the modulation of expression levels of Warts and the phosphorylation of Yorkie.

Abstract

Intense research over the past four years has led to the discovery and characterization of a novel signalling network, known as the Salvador–Warts–Hippo (SWH) pathway, involved in tissue growth control in Drosophila melanogaster. At present, eleven proteins have been implicated as members of this pathway, and several downstream effector genes have been characterized. The importance of this pathway is emphasized by its evolutionary conservation, and by increasing evidence that its deregulation occurs in human tumours. Here, we review the main findings from Drosophila and the implications that these have for tumorigenesis in mammals.

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Figure 1: Tissue that lacks SWH pathway activity develops tumours.
Figure 2: Components of the SWH pathway.

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Acknowledgements

K.H. is a Leukemia and Lymphoma Society Special Fellow, and the recipient of a Career Development Award from the International Human Frontier Science Program Organization. The laboratory of K.H. is supported by the National Health and Medical Research Council of Australia. Work in the laboratory of N.T. is funded by Cancer Research UK.

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Correspondence to Kieran Harvey.

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Glossary

Genetic mosaic screens

The analysis of clones of tissue that harbour homozygous mutations in random genes in an otherwise heterozygous animal that cause a phenotype of interest.

Genetic epistasis experiments

The analysis of dominance of phenotypes generated by the altered function of two or more gene products. Genetic epistasis experiments are often used to predict the order of gene products within signalling pathways.

LIM domain

LIM domains are protein structural domains that are comprised of two contiguous Zinc-finger domains separated by a 2-amino acid residue hydrophobic linker. They are named after their initial discovery in the proteins LIN11, ISL1 and MEC3.

Interommatidial cell

A specific cell type that eventually adopts pigment or bristle cell fates, and surrounds the cone and photoreceptor cells in the Drosophila eye, optically insulating the individual units of the compound eye from each other.

Ectopic proliferation

The generation of daughter cells at a developmental stage or localization within an organ in which cells would normally be quiescent.

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Harvey, K., Tapon, N. The Salvador–Warts–Hippo pathway — an emerging tumour-suppressor network. Nat Rev Cancer 7, 182–191 (2007). https://doi.org/10.1038/nrc2070

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