Reduction of Lobe leads to TORC1 hypoactivation that induces ectopic Jak/STAT signaling to impair Drosophila eye development

Abstract

The TOR and Jak/STAT signal pathways are highly conserved from Drosophila to mammals, but it is unclear whether they interact during development. The proline-rich Akt substrate of 40 kDa (PRAS40) mediates the TOR signal pathway through regulation of TORC1 activity, but its functions in TORC1 proved in cultured cells are controversial. The Drosophila gene Lobe (L) encodes the PRAS40 ortholog required for eye cell survival. L mutants exhibit apoptosis and eye-reduction phenotypes. It is unknown whether L regulates eye development via regulation of TORC1 activity. We found that reducing the L level, by hypomorphic L mutation or heterozygosity of the null L mutation, resulted in ectopic expression of unpaired (upd), which is known to act through the Jak/STAT signal pathway to promote proliferation during eye development. Unexpectedly, when L was reduced, decreasing Jak/STAT restored the eye size, whereas increasing Jak/STAT prevented eye formation. We found that ectopic Jak/STAT signaling and apoptosis are mutually dependent in L mutants, indicating that L reduction makes Jak/STAT signaling harmful to eye development. In addition, our genetic data suggest that TORC1 signaling is downregulated upon L reduction, supporting the idea that L regulates eye development through regulation of TORC1 activity. Similar to L reduction, decreasing TORC1 signaling by dTOR overexpression results in ectopic upd expression and apoptosis. A novel finding from our data is that dysregulated TORC1 signaling regulates the expression of upd and the function of the Jak/STAT signal pathway in Drosophila eye development.

An emerging role for TOR signaling in mammalian tissue and stem cell physiology

“…AKT is also capable of activating TORC1 through the direct phosphorylation of PRAS40, resulting in a reduced ability of PRAS40 to inhibit TORC1 (Kovacina et al, 2003;Sancak et al, 2007;Vander Haar et al, 2007). The inhibition of PRAS40 by AKT is conserved; in Drosophila, the PRAS40 ortholog Lobe regulates TORC1 signaling (Wang and Huang, 2009). Taken together, these findings highlight AKT as a potent upstream activator of TORC1 activity and provide a mechanistic understanding of the elevated TORC1 activity levels that are observed in the majority of cancers in which PI3K-AKT signaling is elevated.…”

MicroRNA-214 Reduces Insulin-like Growth Factor-1 (IGF-1) Receptor Expression and Downstream mTORC1 Signaling in Renal Carcinoma Cells

“…4, A and B). Mutation in the Drosophila Lobe protein, the ortholog of mammalian PRAS40, results in hypoactive mTORC1, indicating that Drosophila PRAS40 positively regulates mTORC1 activity (79). In contrast, in mammalian cells, PRAS40 negatively regulates mTORC1 (46).…”

PRAS40 Is a Functionally Critical Target for EWS Repression in Ewing Sarcoma

“…7E). Silencing of PRAS40 has been shown to result in impaired TORC1 signaling and cell death (19,45). PRAS40 also plays an important role in cell survival among different species (20).…”