Abstract
VPS34 is reported to activate S6K1 and is implicated in regulating cell growth, the mechanisms of which remain elusive. Here, we describe novel mechanisms by which VPS34 upregulates mTOR/S6K1 activity via downregulating TSC2 protein and activating RheB activity. Specifically, upregulation of VPS34 lipid kinase increases local production of ptdins(3)p in the plasma membrane, which recruits PIKFYVE, a FYVE domain containing protein, to ptdins(3)p enriched regions of the plasma membrane, where VPS34 forms a protein complex with PIKFYVE and TSC1. This in turn disengages TSC2 from the TSC1/TSC2 heterodimer, leading to TSC2 ubiquitination and degradation. Downregulation of TSC2 promotes the activation of RheB and mTOR/S6K1. When VPS34 lipid kinase activity is increased by introduction of an H868R mutation, ptdins(3)p production at the plasma membrane is dramatically increased, which recruits more PIKFYVE and TSC1 molecules to the plasma membrane. This results in the enhanced TSC2 ubiquitination and degradation, and subsequent activation of RheB and mTORC1/S6K1, leading to oncogenic transformation. The role played by VPS34 in regulating mTOR/S6K1 activity and cellular transformation is underscored by the fact that the VPS34 kinase dead mutant blocks VPS34-induced recruitment of PIKFYVE and TSC1 to the plasma membrane. This study provides mechanistic insight into the cellular function of VPS34 in regulating oncogenic transformation and important indications for identifying VPS34 specific mutations in human cancers.
Highlights
The mammalian target of rapamycin complex 1 has been established as a critical molecule in the regulation of protein translation, cell cycle progression and cell proliferation [1,2,3,4]
When Vacuolar protein sorting 34 (VPS34) lipid kinase activity is increased by introduction of an H868R mutation, ptdins(3)p production at the plasma membrane is dramatically increased, which recruits more PIKFYVE and TSC1 molecules to the plasma membrane
This results in the enhanced TSC2 ubiquitination and degradation, and subsequent activation of RheB and mammalian target of rapamycin complex 1 (mTORC1)/S6 Kinase 1 (S6K1), leading to oncogenic transformation
Summary
The mammalian target of rapamycin complex 1 (mTORC1) has been established as a critical molecule in the regulation of protein translation, cell cycle progression and cell proliferation [1,2,3,4]. It is believed that deregulation of mTORC1 signaling in tumors is due to either loss of function of upstream tumor suppressor proteins or activating mutations within oncogenes that upregulate mTOR pathway [5]. TSC1 and TSC2 are the tumor-suppressor genes mutated in tumor syndrome TSC (tuberous sclerosis complex). It is recognized that the primary function of the TSC1/TSC2 heterodimer is as a critical negative regulator of mTORC1 activation, where TSC2 exhibits a selective GTPase-activating protein (GAP) activity toward the small GTPase, RheB (Ras homologue enriched in brain). Overexpression of RheB in mammalian cells leads to the activation of mTORC1 in the absence of growth factors [10].
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