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

Abstract

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.