S6 kinases (S6Ks) act to integrate nutrient and insulin signaling pathways and, as such, function as positive effectors in cell growth and organismal development. However, they also have been shown to play a key role in limiting insulin signaling and in mediating the autophagic response. To identify novel regulators of S6K signaling, we have used a Drosophila-based, sensitized, gain-of-function genetic screen. Unexpectedly, one of the strongest enhancers to emerge from this screen was the nuclear receptor (NR), Drosophila hormone receptor 3 (DHR3), a critical constituent in the coordination of Drosophila metamorphosis. Here we demonstrate that DHR3, through dS6K, also acts to regulate cell-autonomous growth. Moreover, we show that the ligand-binding domain (LBD) of DHR3 is essential for mediating this response. Consistent with these findings, we have identified an endogenous DHR3 isoform that lacks the DBD. These results provide the first molecular link between the dS6K pathway, critical in controlling nutrient-dependent growth, and that of DHR3, a major mediator of ecdysone signaling, which, acting together, coordinate metamorphosis.
In biological systems, the execution of morphogenic programs requires coordinated integration of the essential processes of growth, proliferation, and differentiation. Signaling networks embedded within these processes include the insulin and nutrient pathways required for cell growth and the steroid hormone-regulated pathways that control discrete developmental steps. Although these pathways are known to be integrated and coordinated, the molecular bridges that link them remain to be identified. Taking advantage of Drosophila, we performed a genetic screen for novel regulators of the dS6K, which previously has been identified as a key effector of cell growth downstream of insulin and nutrient signaling. Unexpectedly, we identified the nuclear receptor DHR3, a key regulator of morphogenesis, as a potent modulator of dS6K–mediated cell growth. Nuclear receptors typically comprise a DNA–binding domain and a regulatory ligand-binding domain. Here we show that a DHR3 isoform, devoid of the DNA–binding domain is sufficient to potentiate dS6K–mediated cell growth through its ligand-binding domain. We further demonstrate that, like dS6K, DHR3 regulates cell-autonomous growth. These data provide a unique molecular link between steroid-regulated development and nutrient-dependent growth.