Vps34 (PIK3C3)
An enzyme that tags membranes with a small chemical label. Cells need it to build the bag that swallows worn-out parts during autophagy, and some experiments say it also helps tell mTOR that amino acids are around, by a different route than insulin uses.
TL;DR. Vps34 (PIK3C3) appears in 4 curated studies in Oliver's mTOR Atlas: 4 at the molecular level (cells, biochemistry, structure). No study in people is recorded for it in the Atlas yet.
Evidence at a glance
| Evidence | What it means | Studies |
|---|---|---|
| M | Molecular — cells, biochemistry, structure | 4 |
No direct human evidence in the Atlas for this entity yet — everything below rests on animal or molecular work.
Studies
| Year | Evidence | Study |
|---|---|---|
| 2013 | M | ULK1 induces autophagy by phosphorylating Beclin-1 and activating VPS34 lipid kinase RUS2013 The authors asked how the ULK1 kinase switches on autophagy when amino acids are withdrawn. In mouse fibroblasts, amino-acid starvation raised the lipid-kinase activity of VPS34 complexes that contain ATG14L while lowering other VPS34 complexes, and the activation needed ULK kinase activity (lost in ULK-deficient and FIP200-null cells). ULK1 directly phosphorylated Beclin-1 at serine 14 (serine 15 in human), shown with purified kinase, mass spectrometry and a phospho-specific antibody; the mTOR inhibitor Torin1 or amino-acid withdrawal raised this phosphorylation only in cells with ULK activity. Cells reconstituted with non-phosphorylatable Beclin-1 S14A did not increase autophagosomes on amino-acid starvation, and the matching worm mutant (BEC-1 S6A) failed to fully rescue autophagic clearance in C. elegans embryos. The work provided evidence for a signalling chain from mTORC1 inhibition to ULK1, Beclin-1 and the ATG14L-VPS34 complex. Boundary: Mouse and human cell lines, in vitro kinase assays and C. elegans embryos; the mTOR step relies on Torin1 (which blocks mTORC1 and mTORC2) and amino-acid withdrawal. Not tested in mammalian tissues or in people. |
| 2008 | M | Amino acids activate mTOR complex 1 via Ca2+/CaM signaling to hVps34 GUL2008 In cultured human cells, adding amino acids raised the free calcium level inside the cell, and this rise was needed for amino acids to switch on mTORC1 and the lipid kinase hVps34. Calcium-bound calmodulin bound directly to a conserved motif in hVps34, and the authors showed this motif was needed for hVps34 lipid kinase activity and for the increase in mTORC1 signalling. The paper proposed a route from amino acids to mTORC1 that runs through class III PI3K (hVps34) rather than the class I PI3K used by insulin and growth factors. Boundary: Human cell lines only. The calcium/hVps34 route was proposed before the Rag-Ragulator-GATOR model and is not part of the current consensus amino-acid pathway. Drafted from the abstract only. |
| 2005 | M | hVps34 is a nutrient-regulated lipid kinase required for activation of p70 S6 kinase BYF2005 Opens a second, non-canonical route by which amino acids reach mTORC1. The class III PI 3-kinase hVps34 is switched off by amino acid or glucose starvation and by AMPK activation, and is required for S6K1 and 4E-BP1 phosphorylation, yet it sits outside the insulin/class I PI3K input (it does not affect Akt or TSC2 phosphorylation). Boundary: cell lines and knockdown/overexpression only; the step is nutrient-regulated but the sensor itself is not identified. |
| 2005 | M | Amino acids mediate mTOR/raptor signaling through activation of class 3 phosphatidylinositol 3OH-kinase NOB2005 The companion paper to BYF2005, from a different laboratory: the amino acid input to mTORC1 is separate from the insulin input and runs through class 3 PI3K (hVps34), not through class 1 PI3K. Historically important because it states that the amino acid branch is the older one and that insulin signalling was grafted onto it. Boundary: cell lines, pharmacological and knockdown evidence; the later Rag/Ragulator account describes a different route to the same target, and the two accounts are not reconciled in the work this Atlas holds. |
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