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

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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 eitherTSC1orTSC2tumour suppressor genes. Studies inDrosophilaand 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 GTPase1,2. Rheb is a direct target of TSC2 and is negatively regulated by its GTPase-activating protein activity3-5. 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. ReducingDrosophilaTCTP (dTCTP) levels reduces cell size, cell number and organ size, which mimicsDrosophila Rheb(dRheb) mutant phenotypes.dTCTPis genetically epistatic toTsc1anddRheb,but acts upstream ofdS6k,a downstream target ofdRheb.dTCTP directly associates with dRheb and displays guanine nucleotide exchange activity with itin vivoandin vitro.Human TCTP (hTCTP) shows similar biochemical properties compared to dTCTP and can rescuedTCTPmutant phenotypes, suggesting that the function of TCTP in the TSC pathway is evolutionarily conserved. Our studies identify TCTP as a direct regulator ofRheband a potential therapeutic target for TSC disease.

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