PI3K

Gene/Protein · 23 studies in the Atlas

Phosphoinositide 3-kinase; produces signaling lipids downstream of growth-factor receptors; activates Akt and heads the growth-factor arm of the mTOR pathway. It is not upstream of everything: amino-acid sensing at the lysosome, AMPK-mediated energy stress and Ras-MAPK reach mTORC1 by routes that bypass it.

Makes the membrane signal that pulls Akt in. An enzyme that produces signaling lipids right after a growth-factor receptor is switched on. It activates Akt and sits at the top of the growth-signal branch of the mTOR pathway. Nutrients and the cell's energy level reach mTORC1 by other routes that do not pass through it.

p110/p85 heterodimer; PIK3CA is one of the most frequently mutated oncogenes in human cancer. Its output is a lipid, not a phosphoprotein – which is why PTEN reverses it.

TL;DR. PI3K appears in 23 curated studies in Oliver's mTOR Atlas: 1 in people (1 human study); 4 in animal models; 14 at the molecular level (cells, biochemistry, structure); 4 reviews. It has 6 interactions in the curated pathway model.

In the pathway model

6 interactions in the curated mTOR pathway model (2 acting from PI3K, 4 acting on it). Each row is a claim with the evidence behind it; the evidence code is the kind of study, not its quality.

Interaction	Mechanism	Evidence	Studies
PI3K activates Akt/PKB mechanism: recruitment · this link in full · on the map table	That lipid pulls Akt to the cell membrane, where it gets switched on.PIP3 pulls Akt to the membrane, where it gets phosphorylated and activated. Holds under: Mammalian cell study (LIU2015) plus a review (CAN2002). Cell biochemistry; not tested in whole animals or in people by the cited sources. PIP3 recruits Akt; recruitment alone does not activate it. Full activation additionally needs PDK1 (T308) and mTORC2 (S473), so the strength of this link depends on the activity of both of those. plausible in people, not shown directly · settled in the literature	M	CAN2002, LIU2015
PI3K activates mTORC2 mechanism: signal-relay · this link in full · on the map table	The same lipid signal that switches Akt on also switches mTORC2 on – so growth-factor signals hit both complexes.PIP3 made by PI3K binds SIN1 and releases its hold on the kinase site - so growth-factor signalling switches mTORC2 on, not only mTORC1. Holds under: Growth-factor dependence of mTORC2 assembly and activity, shown in mammalian cells. The ribosome requirement (ZIN2011) means the readout is not a clean separation of PI3K input from translational state. plausible in people, not shown directly · emerging, few independent studies	M	LIU2015, ZIN2011, DAL2012, GAN2011
Growth hormone / IGF-1 axis activates PI3K mechanism: signal-relay · this link in full · on the map table	IGF-1 latches onto its own receptor and switches on PI3K, which builds a signalling lipid. Growth hormone works one step further back: it does not land on this receptor itself, it makes the liver release IGF-1, which then does. Insulin takes a receptor of its own into the same arm.IGF-1 docks on the IGF-1 receptor, which recruits IRS proteins and switches on PI3K to make the lipid messenger PIP3. Growth hormone does not use this receptor: it signals through its own receptor and JAK2/STAT5b, and reaches this arm mostly by inducing hepatic IGF-1. The node is drawn as one axis because the Atlas's lifespan evidence comes from interventions that lower the whole axis at once. Holds under: Compressed on purpose: growth hormone and IGF-1 are one node here, but they are not one molecule and they do not share a receptor. GH signals GHR-JAK2-STAT5b and acts on this arm largely by inducing hepatic IGF-1; patients with a homozygous STAT5b mutation have GH insensitivity with low IGF-1 and low IGFBP-3 (Kofoed 2003, PMID 13679528, outside this corpus). The dwarf-mouse lifespan evidence on this axis lowers GH and IGF-1 together, so it does not tell the two apart. Insulin enters the same arm through its own receptor and is drawn separately (INS-PI3K). plausible in people, not shown directly · settled in the literature	M	CAN2002, ROM2001
IRS-1 / IRS-2 activates PI3K mechanism: recruitment · this link in full · on the map table	IRS proteins carry the signal from the insulin receptor to PI3K; without them, the receptor is still there but the wire connecting it is cut.IRS proteins are the adaptors that carry the signal from the insulin/IGF-1 receptor to PI3K. Deplete them and the receptor is still there but the wire is cut. Holds under: Cell studies (TSC1/TSC2-null mouse cells and human cells) plus a review. An adaptor relationship shown in cultured cells; differences between IRS-1 and IRS-2 by tissue are not resolved by these sources. plausible in people, not shown directly · settled in the literature	M	HAR2004, CAN2002
PTEN inhibits PI3K mechanism: functional-consequence · this link in full · on the map table	PTEN erases the lipid signal that PI3K makes. Losing PTEN is one of the most common ways cancers keep this whole pathway switched on without any signal from outside.PTEN erases PIP3, undoing PI3K. Losing PTEN is one of the commonest ways a tumour leaves this whole axis switched on without an upstream signal. Holds under: The arrow is drawn PTEN -> PI3K for readability, but PTEN does not act on the PI3K enzyme. It dephosphorylates PIP3, PI3K's lipid product, so the effect on PI3K signalling is indirect and the edge is a compressed one whose hidden intermediate is PIP3. The canonical biochemical demonstration (Maehama & Dixon, J Biol Chem 1998, PMID 9593664) sits outside this corpus: purified recombinant PTEN dephosphorylates PtdIns(3,4,5)P3 specifically at position 3, and in the same paper PTEN overexpression reduced insulin-induced PIP3 without affecting insulin-induced PI3K activation. The cancer-genetics support in-corpus is mouse (GUE2009). The 'inhibits' label describes the net effect on signalling, not the enzyme itself: PTEN does not inhibit PI3K catalytically, and Maehama & Dixon reported PI3K activation itself unchanged. PTEN dephosphorylates PIP3, PI3K's lipid product, erasing the signal downstream of the enzyme rather than blocking the enzyme's activity. plausible in people, not shown directly · settled in the literature	A	GUE2009
Insulin activates PI3K mechanism: signal-relay · this link in full · on the map table	Insulin lands on its own receptor on the cell surface. The message is passed inward by IRS proteins to PI3K, which builds a signalling lipid, and that is the beginning of the route to mTORC1. This is also the step that breaks when the pathway is overactive for too long.Insulin binds the insulin receptor, which phosphorylates IRS proteins; those recruit PI3K, which makes PIP3 and so starts the arm that reaches mTORC1 through Akt. The step is also where the pathway's best-known feedback lands: S6K1 depletes IRS1/2 and the cell goes deaf to insulin (SHA2004). Holds under: Insulin and IGF-1 share this receptor arm; growth hormone does not, and is kept separate for that reason. The amplitude and the time pattern of the insulin signal are not interchangeable: KUB2012 shows the AKT pathway multiplexes insulin's temporal pattern, so a single arrow understates what the cell reads. Cell and genetic work, plus human physiology for the insulin-resistance end of it. plausible in people, not shown directly · settled in the literature	M	HAR2004, GAR2003, SAU2003, SAN2007, SHA2004

Evidence at a glance

Evidence	What it means	Studies
H	Human study	1
A	Animal model	4
M	Molecular — cells, biochemistry, structure	14
R	Review — secondary literature, not a new result	4

Studies

Year	Evidence	Study
2026	H	Leniolisib and rapamycin in Activated PI3-Kinase-δ-syndrome: a retrospective ESID registry-based analysis RIV2026 In a 95-patient ESID registry of Activated PI3Kδ Syndrome (APDS), rapamycin and the targeted PI3Kδ inhibitor leniolisib produced comparable overall response rates for lymphoproliferation (67% vs 64%), but treatment-limiting adverse events occurred only in the rapamycin-treated group; lymphoma cases were observed during follow-up in the cohort.
2026	A	mTOR inhibition augments antitumor immune effector response by reprogramming the TP53-mutant, immune-cold HNSCC tumor microenvironment NAT2026 In syngeneic TP53-mutant HNSCC mouse models, the mTOR inhibitor everolimus reprogrammed the immune-cold tumor microenvironment: it increased CD8+ T cell and dendritic cell infiltration, reduced Tregs and HIF-1α/VEGFA-driven MDSC recruitment, boosted TNF-α/CXCL10 chemokine signaling, and reduced PD-1/PD-L1 expression — restoring T-cell cytotoxic competence and suppressing tumor growth.
2026	A	LncRNA DLX6-AS1 promotes necroptosis through PI3K/AKT/mTOR signaling pathway in myocardial ischemia/reperfusion injury mice SU2026 LncRNA DLX6-AS1 activates PI3K/AKT/mTOR signaling to promote necroptosis in myocardial ischemia-reperfusion injury; inhibiting DLX6-AS1 suppresses necroptosis and protects cardiomyocytes.
2026	A	Corilagin attenuates osteoarthritis progression by coordinating NF-κB inhibition with PI3K/AKT/mTOR-associated autophagy restoration. ZHOU2026B Corilagin restores chondrocyte autophagic flux and ECM synthesis by inhibiting PI3K/AKT/mTOR and NF-κB signalling, reducing cartilage erosion and OARSI scores in the mouse DMM osteoarthritis model.
2026	A	Anti-breast cancer effects of the Xingxiao Pill are associated with inhibition of the ErbB3/PI3K/AKT/mTOR pathway, modulation of amino acid metabolism, and promotion of apoptosis. ZHANG2026C Xingxiao Pill inhibited 4T1 breast cancer growth in vitro and in vivo by suppressing ErbB3/PI3K/AKT/mTOR signalling and reshaping amino acid metabolism; cinnamic acid and palmitic acid were identified as constituents that bind mTOR.
2026	R	Decoding the PI3K/Akt/mTOR-JAK/STAT signaling axis in multiple sclerosis: mechanistic crosstalk and therapeutic opportunities. BANERJEE2026 Review mapping the mechanistic crosstalk between PI3K/Akt/mTOR and JAK/STAT pathways in MS neuroinflammation, identifying dual-pathway mTOR targeting as a therapeutic opportunity to reduce immune dysregulation and demyelination.
2026	M	Transcriptional modulation of the PI3K/AKT/mTOR signaling pathway mediated by HPV16 E5, E6, and E7 oncogene expression in breast cancer. DEOLIVEIRA2026 In breast tumour tissue (48 of 92 patients with usable RNA), HPV16 oncogene expression was associated with higher PI3K and lower mTOR transcript levels. The design is correlational and measures mRNA only, so it does not show that the virus activates the mTOR pathway.
2026	M	IGF2BP3-Mediated m6A Modification of OLR1 mRNA Promotes Immune Evasion in CRC via the PI3K/AKT/mTOR Pathway CHEN2026B IGF2BP3 stabilizes OLR1 via m6A RNA modification, activating PI3K/AKT/mTOR signaling which suppresses CD8+ T cell anti-tumor activity and drives immune evasion in colorectal cancer.
2026	M	Brucella suis vaccine strain 2 promotes intracellular proliferation by inducing M2 macrophage polarization and autophagy through PI3K/Akt/mTOR signalling. LI2026B Brucella suis vaccine strain 2 drives mixed M1/M2 macrophage polarisation and autophagic activation in BV2 cells; the M2 state and autophagy synergistically promote intracellular bacterial replication through PI3K/Akt/mTOR signalling.
2019	R	The PI3K-AKT network at the interface of oncogenic signalling and cancer metabolism HOX2019 Review of the PI3K-AKT-mTOR network at the interface of oncogenic signalling and metabolism.
2016	M	A systems study reveals concurrent activation of AMPK and mTOR by amino acids DAL2016 Adding amino acids back to starved cells switched on AMPK, PI3K and mTORC2 acutely and independently of mTORC1, at the same time as mTOR. AMPK activation ran through CaMKK-beta and, under amino acid sufficiency, AMPK kept autophagy going via ULK1. So the textbook picture of AMPK and mTORC1 as simple opposites does not hold in the first minutes after feeding - which matters for how the AMPK-ULK1 feedback arm behaves over time.
2015	R	Regulation of mTORC1 by PI3K signaling DIB2015 Review of mTORC1 regulation by PI3K signalling.
2012	M	A dynamic network model of mTOR signaling reveals TSC-independent mTORC2 regulation DAL2012 A time-resolved, data-fitted model of the whole core insulin-mTOR network, including the mTORC1 negative feedback loop onto PI3K. Perturbing it in silico and in cells showed that TSC1-TSC2 is not a regulator of mTORC2, directly or through the feedback loop, and that mTORC2 activation runs through a PI3K variant insensitive to that loop. One of the few places where the feedback loops in the atlas are treated as a dynamical system rather than a diagram.
2011	M	Activation of mTORC2 by association with the ribosome ZIN2011 mTORC2 is activated by direct association with the ribosome downstream of PI3K.
2011	M	Evidence for direct activation of mTORC2 kinase activity by phosphatidylinositol 3,4,5-trisphosphate GAN2011 PIP3 directly stimulates mTORC2 kinase activity, linking PI3K to mTORC2.
2010	M	The mTOR kinase determines effector versus memory CD8+ T cell fate by regulating the expression of transcription factors T-bet and Eomesodermin RAO2010 Working with naive OT-I CD8 T cells stimulated by antigen plus B7.1, the authors showed that IL-12 both raised and prolonged mTOR phosphorylation and S6K1 Thr389 phosphorylation out to 48 hours, and that this required PI3K throughout and STAT4 for the late phase. Rapamycin, added at the start or only at 12 hours, blocked the sustained expression of T-bet and with it the heritable type I effector programme, while raising Eomesodermin and producing cells with a memory-precursor phenotype (CD62L high, KLRG1 low, Bcl-2 high). Restoring T-bet by a tamoxifen-inducible construct brought back IFN-gamma production and lowered Eomesodermin, which places T-bet downstream of mTOR in this system. After transfer, the rapamycin-treated cells persisted better, gave stronger antigen-recall responses, and more than 78 percent of recipients stayed tumour-free to day 120 against 50 percent fatality with IL-12-conditioned effector cells. Boundary: mouse CD8 T cells, one TCR-transgenic system with pharmacological mTOR inhibition in vitro before transfer; the transplantable E.G7 tumour is a model, not a treatment result in people, and the memory-precursor phenotype faded by day 40 after transfer.
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.
2002	R	The phosphoinositide 3-kinase pathway CAN2002 Review establishing PI3K as a central signaling hub controlling cell survival, metabolism, and growth downstream of growth-factor receptors and upstream of Akt and mTOR.
2002	M	TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling INO2002 Akt directly phosphorylates and inactivates TSC2, disrupting the TSC1-TSC2 complex and releasing its inhibition of mTOR - the link between growth-factor/insulin signaling and mTORC1 activation.
2002	M	Mammalian cell size is controlled by mTOR and its downstream targets S6K1 and 4EBP1/eIF4E FIN2002 mTOR controls mammalian cell size through its downstream translational targets S6K1 and 4E-BP1/eIF4E.
2002	M	Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway MAN2002 The authors combined biochemistry with a search for Akt consensus motifs and picked out tuberin, the TSC2 tumour suppressor protein, as a likely Akt substrate. They showed that activating PI3K leads to phosphorylation of tuberin at sites matching the Akt motif, and that Akt can phosphorylate tuberin both in vitro and in cells. Two of these sites, S939 and T1462, were regulated by PI3K, and T1462 stayed phosphorylated in tumour cell lines lacking PTEN. A tuberin mutant without the main PI3K-dependent sites blocked activation of S6K1. Together with papers from other labs in the same months, this was one of the early papers to link growth-factor signalling through Akt to the TSC complex and mTORC1 output. Boundary: cultured mammalian cells and in vitro kinase assays, with overexpressed tuberin mutants; no whole-animal or human tissue data.
2001	M	Mediation of IGF-1-induced skeletal myotube hypertrophy by PI(3)K/Akt/mTOR and PI(3)K/Akt/GSK3 pathways ROM2001 Shows IGF-1 drives muscle fiber hypertrophy through Akt, via both the mTOR and GSK3 branches, in cultured myotubes, establishing mTOR as a central node for muscle growth signaling.
2000	M	Regulation of cellular growth by the Drosophila target of rapamycin dTOR ZHA2000 The authors showed that fly TOR (dTOR) is needed inside each cell for normal growth and proliferation during larval development. dTOR was also needed for the extra cell growth caused by activating PI3K signalling. As in mammalian cells, dTOR kinase activity was needed for growth factor-dependent phosphorylation of S6 kinase in vitro, and overexpressing S6 kinase rescued dTOR mutant flies to viability. dTOR loss also produced signs of amino acid starvation, such as smaller nucleoli and lipid droplet clumping in the fat body, plus a cell-type-specific cell cycle arrest that cyclin E could bypass. The authors proposed that dTOR links growth factor signalling to nutrient availability during development. Boundary: Drosophila larvae and in vitro kinase assays; rescue relied on overexpression of S6 kinase, and results are not shown in mammals here.

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Barton, O. (2026). PI3K [Entity page]. In Oliver's mTOR Atlas [Data set]. https://mtor-atlas.org/gene/pi3k/ · Dataset DOI 10.5281/zenodo.22059963

@misc{atlas_gene_pi3k,
  author       = {Barton, Oliver},
  title        = {{Oliver's mTOR Atlas}: PI3K},
  howpublished = {Entity page in a data set},
  year         = {2026},
  url          = {https://mtor-atlas.org/gene/pi3k/},
  doi          = {10.5281/zenodo.22059963}
}

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