Generic PI3K-AKT-mTOR signaling module

A taxon-neutral decomposition of the class I PI3K-AKT-mTOR signaling axis, the reusable survival/growth/metabolism arm deployed downstream of many receptor systems. Like the Ras-MAPK cascade it is a "sidecar" module: the same PI3K->PIP3->AKT->mTOR core is engaged by receptor tyrosine kinases (insulin/IGF, EGFR, PDGFR), by insulin-receptor-substrate (IRS) adaptors, by cytokine receptors signaling through JAKs, by GPCRs (class IB PI3K-gamma), and by active Ras. The module captures: (1) recruitment and activation of class I PI3K (p110 catalytic + p85 regulatory subunits) at a receptor phosphotyrosine, via IRS, or by Ras; (2) PI3K conversion of PIP2 to the second messenger PIP3; (3) PIP3-dependent membrane recruitment of PH-domain proteins PDK1 and AKT; (4) AKT activation by dual phosphorylation (PDK1 on Thr308, mTORC2 on Ser473); (5) AKT-driven activation of mTORC1 via inhibition of the TSC1/2 GAP and consequent Rheb-GTP accumulation; (6) downstream outputs - mTORC1 activation of S6K and 4E-BP1 (translation/growth) and AKT inhibition of FOXO and GSK3 (survival, metabolism); and (7) negative regulation, principally the lipid phosphatase PTEN (which removes the 3-phosphate from PIP3), plus PHLPP (AKT dephosphorylation) and the TSC complex. Grounded in GO:0043491 (phosphatidylinositol 3-kinase/protein kinase B signal transduction) and GO:0031929 (TOR signaling).

MODULE:pi3k_akt_mtorDRAFTSignaling Pathwaymodules/pi3k_akt_mtor.yaml
phosphatidylinositol 3-kinase/protein kinase B signal transductionGO:0043491 TOR signalingGO:0031929
GO:0043491
phosphatidylinositol 3-kinase/protein kinase B signal transduction
The module is grounded in the GO biological process term for PI3K/protein kinase B (AKT) signal transduction.
GO:0031929
TOR signaling
The growth-control output tier is grounded in TOR signaling, the mTOR-centered control of translation and cell growth.
GO:0046934
1-phosphatidylinositol-4,5-bisphosphate 3-kinase activity
The initiating biochemistry is class I PI3K phosphorylation of PIP2 at the 3-position to generate the PIP3 second messenger.
PANTHER:PTN000683254
PAINT AKT-family kinase ancestral node
Local PAINT IBD seed rows place curated AKT exemplars in a serine/threonine kinase node with protein kinase activity and intracellular signal transduction terms, anchoring the AKT effector tier where the cache supports it.
PANTHER:PTN000959472
PAINT PTEN phosphatase node
Local PAINT IBD seed rows place the curated PTEN exemplar in PTHR12305 node PTN000959472 with protein tyrosine phosphatase activity, anchoring the lipid/protein phosphatase negative-regulatory tier where supported.

This is a reusable sidecar module referenced as a branch-point interface by the JAK-STAT signaling module (MODULE:jak_stat_signaling): JAK-phosphorylated receptor tyrosines (often via IRS adaptors, e.g. for IL-4 and growth-hormone receptors) recruit class I PI3K and fork into this axis in parallel with STAT activation. The same module is deployed by RTKs, GPCRs, and active Ras. Concrete realizations specialize the PI3K isoform, the recruitment route (direct pY vs IRS vs Ras), the AKT paralog, and the effector set. Representative UniProt members and PTEN's lipid-phosphatase terms were verified against curated reviews in this repository; tiers without a verified local exemplar are given as family descriptors.

7Nodes
6Parts
0Variant Sets
0Variants
7Annotons
5Connections

Derived QC

Recommended-field compliance

100.0% recommended fields populated

All recommended fields populated.

Module deep research

✗ none found

No MODULE:pi3k_akt_mtor deep-research report alongside the module YAML.

Leaf nodes lacking representative members

4 leaf node(s) with no concrete protein grounding:

Template conformance

✓ every declared conforms_to bundle matches its template motif.

Function consistency and core coverage

2 gene-function check(s) reflected in core functions · 0 conflict(s) · 3 evidence or coverage gap(s) (7 comparison(s))

Retained noncore functions are reported separately; they do not require promotion to core functions. Support from representative genes does not establish conservation across the whole family. Missing reviews or identifiers leave a claim unverified.

AnnotonParticipantFunctionAssessment
pip3_effector_recruitment ANY_WITH_DOMAIN
Gene 		phosphatidylinositol-3,4,5-trisphosphate binding
No function ID 		Participant Unchecked
No direct UniProt participant to compare. Abstract selectors and complex-wide activities cannot be inferred from donor or subunit gene reviews.
akt_kinase AKT1
UniProtKB:P31749
Family Representative 		protein serine/threonine kinase activity
GO:0004674 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
mtorc1_kinase PROTEIN_COMPLEX
Gene 		protein serine/threonine kinase activity
GO:0004674 		Participant Unchecked
No direct UniProt participant to compare. Abstract selectors and complex-wide activities cannot be inferred from donor or subunit gene reviews.
pten_role PTEN
UniProtKB:P60484
Gene 		phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase activity
GO:0016314 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
pi3k_recruitment class I PI3K (p110/p85)
Family 		insulin receptor substrate binding
GO:0043560 		Family Id Missing
The family has no identifier linking it to a curated family review.
pi3k_lipid_kinase class I PI3K catalytic subunit
Family 		1-phosphatidylinositol-4,5-bisphosphate 3-kinase activity
GO:0046934 		Family Id Missing
The family has no identifier linking it to a curated family review.
akt_kinase AKT/PKB kinases
Family 		protein serine/threonine kinase activity
GO:0004674 		Family Id Missing
The family has no identifier linking it to a curated family review.

Feedback loops (advisory, prose-driven: a regulator counts as "feedback" when its own description says so)

✓ every negative regulator described as feedback has an upstream edge closing the loop.

  • pi3k_negative_regulation ⊣ pi3k_activation [input]
    pi3k_negative_regulation is a negative regulator with no upstream edge (not described as feedback)

Gene-review completeness (2/2 grounded genes reviewed)

0 complete review(s) · 2 with deep research · 0 missing review · 0 reviewed but lacking deep research

Gene Review Complete Deep research
AKT1 P31749 ✓ 414/445 ✓
PTEN P60484 ✓ 192/199 ✓

Details

Context
metazoaNCBITaxon:33208
plasma membraneGO:0005886 cytosolGO:0005829
PI3K-AKT-mTOR signaling axisSignaling Pathwaypi3k_akt_mtor
phosphatidylinositol 3-kinase/protein kinase B signal transductionGO:0043491 TOR signalingGO:0031929
Context
metazoaNCBITaxon:33208
plasma membraneGO:0005886 cytosolGO:0005829

Connections

PI3K-generated PIP3 recruits PDK1 and AKT to the membrane.
pip3_akt_recruitment -> akt_activation Provides Input For
Membrane co-localization enables PDK1/mTORC2 phosphorylation of AKT.
AKT inhibits TSC1/2, activating Rheb-mTORC1.
mtorc1_activation -> akt_mtor_output Provides Input For
mTORC1 (with AKT) drives the translation/growth/survival output.
pi3k_negative_regulation -> pi3k_activation Negatively Regulates
PTEN dephosphorylates PIP3, the principal off-switch for the axis.
Part 1: class I PI3K recruitment and activation
Class I PI3K recruitment and activationReactionpi3k_activation

Class IA PI3K (p110 catalytic subunit, e.g. PIK3CA, with a p85 regulatory subunit, e.g. PIK3R1) is recruited to the membrane by binding of the p85 SH2 domains to receptor or IRS phosphotyrosines, and can be co-activated by GTP-bound Ras. Class IB PI3K-gamma is recruited by GPCR Gbeta-gamma. This activates the lipid kinase.

phosphatidylinositol 3-kinase complexGO:0005942

Annotons

PI3K regulatory-subunit docking
pi3k_recruitment
Participant: Family: class I PI3K (p110/p85)
Family:
class I PI3K (p110/p85) Heterodimeric class I phosphoinositide 3-kinases that produce PIP3.

Function

insulin receptor substrate bindingGO:0043560 p85 SH2 recognition of IRS/receptor phosphotyrosine docking sites (one of several recruitment routes).

Membrane recruitment that positions PI3K at its lipid substrate.

PI3K lipid kinase activity
pi3k_lipid_kinase
Participant: Family: class I PI3K catalytic subunit
Family:
class I PI3K catalytic subunit p110 catalytic subunits (PIK3CA/PIK3CB/PIK3CD/PIK3CG).

Function

1-phosphatidylinositol-4,5-bisphosphate 3-kinase activityGO:0046934
Substrates: phosphatidylinositol 4,5-bisphosphate (PIP2)
Products: phosphatidylinositol 3,4,5-trisphosphate (PIP3)

Locations

plasma membraneGO:0005886

Generates the PIP3 second messenger.

Part 2: PIP3 second messenger and AKT/PDK1 recruitment
PIP3 generation and PH-domain recruitment of PDK1/AKTRegulatory Steppip3_akt_recruitment

PIP3 accumulates in the inner leaflet and recruits PH-domain-containing proteins - the kinase PDK1 (PDPK1) and AKT - to the membrane, bringing the kinase and its activating kinase into proximity.

Annotons

PIP3-dependent membrane recruitment
pip3_effector_recruitment
Participant: Any With Domain: pleckstrin homology (PH) domain
Required Domain:
pleckstrin homology (PH) domain PH domains that bind PIP3 and mediate membrane recruitment of PDK1 and AKT.

Function

phosphatidylinositol-3,4,5-trisphosphate binding PH-domain recognition of PIP3 at the membrane.

Converts the lipid signal into co-localization of AKT and its activators.

Part 3: AKT activation
AKT/PKB dual-site activationReactionakt_activation

Membrane-recruited AKT (AKT1/2/3) is activated by PDK1 phosphorylation of Thr308 in its activation loop and by mTORC2 phosphorylation of Ser473 in its hydrophobic motif, yielding the active kinase.

Annotons

AKT serine/threonine kinase activity
akt_kinase
Participant: Family: AKT/PKB kinases
Family:
AKT/PKB kinases AKT1, AKT2, AKT3 serine/threonine protein kinases.
Representative Members: AKT1UniProtKB:P31749

Function

protein serine/threonine kinase activityGO:0004674
Targets: TSC2 FOXO transcription factors GSK3

Central effector kinase relaying PIP3 to growth/survival substrates.

Part 4: mTORC1 activation via TSC/Rheb
mTORC1 activationReactionmtorc1_activation

Active AKT phosphorylates and inhibits the TSC1/TSC2 GTPase-activating complex, relieving its suppression of the small GTPase Rheb; Rheb-GTP then activates mTOR complex 1 (mTORC1).

TOR signalingGO:0031929

Annotons

mTORC1 kinase activity
mtorc1_kinase
Participant: Protein Complex: mTOR complex 1 (mTORC1)
Protein Complex:
mTOR complex 1 (mTORC1) mTOR-RAPTOR growth-control kinase complex activated downstream of AKT.

Function

protein serine/threonine kinase activityGO:0004674
Targets: S6K1 (RPS6KB1) 4E-BP1 (EIF4EBP1)

Master growth-control kinase driving translation and biosynthesis.

Part 5: downstream growth/survival/metabolic output
AKT/mTORC1 effector outputRegulatory Stepakt_mtor_output

mTORC1 activates S6K1 and inhibits 4E-BP1 to promote cap-dependent translation and cell growth; AKT phosphorylates and inhibits FOXO transcription factors (suppressing pro-apoptotic genes) and GSK3 (altering metabolism and stability of many substrates), together producing the survival/growth/metabolic program.

Annotons

Translation, survival, and metabolic effectors
akt_mtor_effectors
Participant: Any Participant: S6K1, 4E-BP1, FOXO1/3, GSK3 and related effectors.
S6K1, 4E-BP1, FOXO1/3, GSK3 and related effectors.

Executes the pro-growth/pro-survival output of the axis.

Part 6: negative regulation
Negative regulation of PI3K-AKT signalingRegulatory Steppi3k_negative_regulation

The axis is restrained chiefly by PTEN, the lipid phosphatase that dephosphorylates PIP3 back to PIP2 (the principal off-switch), and by AKT-directed phosphatases (PHLPP) and the TSC complex.

Annotons

PTEN PIP3 3-phosphatase
pten_role
Participant: Gene Product: PTEN
Gene Product:
PTENUniProtKB:P60484

Function

phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase activityGO:0016314
Substrates: phosphatidylinositol 3,4,5-trisphosphate (PIP3)
Products: phosphatidylinositol 4,5-bisphosphate (PIP2)

Principal negative regulator; removes the 3-phosphate from PIP3 to shut off the axis. A tumor suppressor frequently lost in cancer.