Drosophila TCTP is essential for growth and proliferation through regulation of dRheb GTPase

Abstract

Cellular growth and proliferation are coordinated during organogenesis. Misregulation of these processes leads to pathological conditions such as cancer. Tuberous sclerosis (TSC) is a benign tumour syndrome caused by mutations in either TSC1 or TSC2 tumour suppressor genes. Studies in Drosophila and other organisms have identified TSC signalling as a conserved pathway for growth control. Activation of the TSC pathway is mediated by Rheb (Ras homologue enriched in brain), a Ras superfamily GTPase. Rheb is a direct target of TSC2 and is negatively regulated by its GTPase-activating protein activity. However, molecules required for positive regulation of Rheb have not been identified. Here we show that a conserved protein, translationally controlled tumour protein (TCTP), is an essential new component of the TSC-Rheb pathway. Reducing Drosophila TCTP (dTCTP) levels reduces cell size, cell number and organ size, which mimics Drosophila Rheb (dRheb) mutant phenotypes. dTCTP is genetically epistatic to Tsc1 and dRheb, but acts upstream of dS6k, a downstream target of dRheb. dTCTP directly associates with dRheb and displays guanine nucleotide exchange activity with it in vivo and in vitro. Human TCTP (hTCTP) shows similar biochemical properties compared to dTCTP and can rescue dTCTP mutant phenotypes, suggesting that the function of TCTP in the TSC pathway is evolutionarily conserved. Our studies identify TCTP as a direct regulator of Rheb and a potential therapeutic target for TSC disease.

The Translational Controlled Tumour Protein TCTP: Biological Functions and Regulation

“…The importance of TCTP in early development was also demonstrated in Drosophila, where TCTP-knockdown experiments established a role for TCTP in the regulation of cell size and number, organ growth (Hsu et al 2007) and development (Hong and Choi 2013). Interaction partners of TCTP in this context are the small GTPase Rheb, an upstream regulator of mTOR (mechanistic target of rapamycin), and 14-3-3 proteins (Le et al 2016).…”

“…The involvement of TCTP in cellular growth regulation is documented in various settings. One example, already mentioned above, described the role for TCTP in the regulation of cell size and number, as well as organ growth (Hsu et al 2007) and development (Hong and Choi 2013) in Drosophila. In plants, it was shown that knockout of TCTP resulted in a phenotype with a slow vegetative growth and impaired pollen tube growth (Berkowitz et al 2008).…”

“…It is part of a complex signalling network that regulates several anabolic processes, inclusive of protein synthesis (Laplante and Sabatini 2012;Zoncu et al 2011). In 2007, Hsu et al published a paper describing TCTP in Drosophila as a direct activator of this pathway, acting as a guanine nucleotide exchange factor (GEF) for the small GTPase Rheb, upstream of mTORC1 (Hsu et al 2007). Consistent with this, reducing Drosophila TCTP levels reduced cell size, cell number and organ size, similar to Rheb mutant phenotypes.…”

“…Briefly, TCTP overexpression was found to activate the Ras/Raf/ERK, the PLC-γ and the PI3K/Akt growth signalling pathways in HeLa cells (Kim et al 2009b). Also, Hsu et al described TCTP in Drosophila as an activator of the small GTPase Rheb, an upstream activator of the mTORC1 pathway, and based on this, implicated TCTP in growth regulation (Hsu et al 2007). However, other follow-up studies could not confirm some of the findings in mammalian cells (Wang et al 2008;Rehmann et al 2008).…”

“…Blocking this pathway in itself will inhibit TCTP expression, since TCTP mRNA translation is regulated through the mTOR pathway (Bommer et al 2015). In Drosophila, TCTP was described as a positive regulator of the mTOR pathway via the small GTPase Rheb (Hsu et al 2007); it is therefore possible that TCTP and mTOR are in a positive feedback loop (Kobayashi et al 2014), which would be disrupted by treatment with sertraline or thioridazine. In a very recent paper, two additional antihistaminic drugs, buclizine and levomepromazine, were reported to inhibit cancer cell growth by binding to TCTP and by inducing cell differentiation (Seo and Efferth 2016).…”