The Mob superfamily has more than 130 members that are highly conserved through evolution, but their functions are not well understood. Lai and colleagues report a newly discovered family member, MATS (for 'Mob as tumour suppressor'), that has a possible role as a coactivator of protein kinases such as the tumour suppressor WTS.

The authors identified the mats gene in fruitflies as a spontaneous lethal muation that increased cell proliferation and caused tumour development in many organs. The mats-mutant flies have high levels of key cell-cycle regulators such as cyclins, and show impaired cellular differentiation.

In fly eye discs, mats is necessary to downregulate transcription of diap1, which encodes a caspase inhibitor that is required for cell survival. Furthermore, introducing the mats mutation into flies that already have an apoptosis-promoting defect cancelled out the effects of this defect. This indicates that mats facilitates cell death and explains why loss of mats might contribute to tumour growth.

Genetic-mapping experiments in the fruitfly identified mats as the CG13852 gene, an assignment that was confirmed using CG13852 cDNA to rescue the mats mutants. Phylogenetic analysis showed that the mats genes form a highly conserved subgroup of the Mob-gene superfamily, with human and plant homologues showing 87% and 64% identity to fly mats, respectively. So, MATS protein function is likely to be conserved, and, in fact, the human homologue MATS1 efficiently suppressed the phenotype of mats mutant flies.

Evidence to support the model that MATS might function as a tumour suppressor came from the identification of a destabilizing mutation of MATS1 in a human melanoma sample, and a null mutation of Mats1 in a mouse mammary carcinoma.

mats-mutant flies have similar phenotypes to flies that are mutant for components of the HPO–SAV–WTS signalling pathway, which regulates cell proliferation and apoptosis, so the authors investigated the relationship between mats and wts. They found that mats and wts interact synergistically to control cell proliferation and apoptosis, and that MATS forms a complex with WTS.

Other Mob-family proteins have been shown to stimulate the catalytic activity of protein kinases. Similarly, MATS markedly stimulated the kinase activity of WTS, and human MATS1 was as effective as fly MATS. WTS also seemed to phosphorylate both itself and MATS/MATS1. Furthermore, inhibiting phosphatase activity notably increased WTS kinase activity, which indicates that phosphorylation of MATS and/or WTS is crucial for WTS function.

So, MATS seems to function as an activating subunit of the WTS kinase in restricting cell proliferation and promoting apoptosis. Moreover, as its effects on growth inhibition and tumour suppression seem to be evolutionarily conserved, MATS might well turn out to be important in human cancers.