TUFT1 interacts with RABGAP1 and regulates mTORC1 signaling

The mammalian target of rapamycin (mTOR) pathway is commonly activated in human cancers. The activity of mTOR complex 1 ( mTORC1) signaling is supported by the intracellular positioning of cellular compartmentsand vesicle trafficking, regulated by Rab GTPases. Here we showed that tuftelin1 (TUFT1) was involved in the activation of mTORC1through modulating the Rab GTPase-regulated process. TUFT1 promoted tumor growth and metastasis. Consistently, the expression of TUFT1 correlated with poor prognosis in lung, breast and gastric cancers. Mechanistically, TUFT1 physically interacted with RABGAP1, thereby modulating intracellular lysosomal positioning and vesicular trafficking, and promoted mTORC1signaling. In addition, expression of TUFT1 predicted sensitivity to perifosine, an alkylphospholipid that alters the composition of lipid rafts. Perifosinetreatment altered the positioning and trafficking of cellular compartmentsto inhibit mTORC1. Our observations indicate that TUFT1 is a key regulator of the mTORC1pathway and suggest that it is a promising therapeutic target or a biomarker for tumor progression.