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Appropriate cell number and organ size in a multicellular organism are determined by coordinated cell growth, proliferation, and apoptosis. Disruption of these processes can cause cancer. Recent studies have identified the Large tumor suppressor (Lats)/Warts (Wts) protein kinase as a key component of a pathway that controls the coordination between cell proliferation and apoptosis. Here we describe growth inhibitory functions for a Mob superfamily protein, termed Mats (Mob as tumor suppressor), in Drosophila. Loss of Mats function results in increased cell proliferation, defective apoptosis, and induction of tissue overgrowth. We show that mats and wts function in a common pathway. Mats physically associates with Wts to stimulate the catalytic activity of the Wts kinase. A human Mats ortholog (Mats1) can rescue the lethality associated with loss of Mats function in Drosophila. As Mats1 is mutated in human tumors, Mats-mediated growth inhibition and tumor suppression is likely conserved in humans.

The transcription repressor Tramtrack (TTK) is found in cone cells but not photoreceptor cells of the Drosophila eye. We show that down-regulation of TTK expression occurs in photoreceptor cells and is required for their fate determination. Down-regulation requires the presence of Phyllopod (PHYL), which is induced by the RAS pathway, and Seven In Absentia (SINA). Loss of either gene causes accumulation of TTK in photoreceptor cells, and TTK does not accumulate in cone cells if both PHYL and SINA are present. We report that SINA and PHYL promote ubiquitination and rapid degradation of TTK by the proteasome pathway in cell culture, and both SINA and PHYL bind to the N-terminal domain of TTK. These results argue that photoreceptor differentiation is regulated by the RAS pathway through targeted proteolysis of the TTK repressor.

Loss-of-function mutations in the yan gene result in the differentiation of supernumerary photoreceptors in the Drosophila eye. The yan gene encodes a protein with an ETS DNA-binding domain that accumulates in the nuclei of undifferentiated cells during the early stages of eye development. Our data suggest that yan functions as a cell-autonomous negative regulator of photoreceptor development; in the presumptive R7 and cone cells, yan appears to act antagonistically to the proneural signal mediated by sevenless and Ras1.