Akt/PKB
Key kinase downstream of PI3K in growth signaling; activated by mTORC2.
The main 'grow' relay from growth factors.
T308 by PDK1 and S473 by mTORC2. Recruitment and activation are separate events – a distinction the older Atlas diagram blurred.
Evidence at a glance
| Evidence | What it means | Studies |
|---|---|---|
| A | Animal model | 1 |
| M | Molecular — cells, biochemistry, structure | 11 |
| R | Review — secondary literature, not a new result | 1 |
No direct human evidence in the Atlas for this entity yet — everything below rests on animal or molecular work.
Studies
| Year | Evidence | Study |
|---|---|---|
| 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 | M | Firefox, a protein encoded by circular RNA circPVT1, is essential for MYC-driven oncogenesis TIW2026 A micropeptide (Firefox/FFX) encoded by the circular RNA circPVT1 stimulates AKT-mTORC1 signaling and cap-dependent translation to sustain MYC protein abundance and transcriptional output. FFX depletion reduces MYC levels and impairs tumor growth in MYC-amplified xenograft models, identifying an mTORC1-linked vulnerability in MYC-driven cancers. |
| 2009 | M | DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival PET2009 Identified DEPTOR as a built-in brake on BOTH mTOR complexes. The twist: in some multiple myelomas DEPTOR is overexpressed, which by relieving a feedback loop actually keeps pro-survival Akt signaling ON - a neat example of how an 'inhibitor' can be co-opted by cancer. |
| 2009 | M | Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2 FEL2009 The parallel discovery to Thoreen 2009 (same year), from the Shokat lab. Their TORKinibs (PP242, PP30) block mTOR's active site, hitting both complexes and shutting down cap-dependent translation that rapamycin misses. Together these two papers established a whole new drug class beyond rapamycin. |
| 2007 | M | PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase SAN2007 Identified PRAS40 as the missing insulin-controlled brake INSIDE mTORC1. When insulin is absent PRAS40 clamps the complex shut; insulin makes Akt phosphorylate PRAS40, releasing the brake so Rheb can fully switch mTORC1 on. Explained how hormone signals set the exact strength of mTORC1 activity. |
| 2006 | M | Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB SAR2006 The molecular explanation for rapamycin's dark side. Short-term rapamycin only hits mTORC1, but LONG-term treatment also strips down mTORC2 in many cells, cutting Akt signaling. This is the mechanistic root of the insulin-resistance side effect later shown in mice (see Lamming 2012) - crucial for anyone dosing rapamycin for longevity. |
| 2006 | M | Ablation in mice of the mTORC components raptor, rictor, or mLST8 reveals that mTORC2 is required for signaling to Akt-FOXO and PKCalpha, but not S6K1 GUE2006 The foundational genetic 'dissection' of the two complexes in living mice. Deleting Raptor was lethal early (mTORC1 essential); deleting Rictor or mLST8 selectively knocked out mTORC2 signaling to Akt and PKCalpha but spared S6K1. This cleanly assigned jobs to each complex and showed mLST8 is an mTORC2-specific requirement in mice. |
| 2005 | M | Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex SAR2005 The rictor-mTOR complex (mTORC2) directly phosphorylates Akt/PKB on Ser473, regulating cell survival. |
| 2004 | M | Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton SAR2004 Discovery of Rictor and the SECOND mTOR complex, mTORC2. Crucially showed this complex is NOT blocked by rapamycin and does not use Raptor - it controls the cytoskeleton via PKC. This is the paper that split mTOR biology into 'two faces' at the molecular level. |
| 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. |
| 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 specifically through the Akt-mTOR pathway, establishing mTORC1 as a central node for muscle growth signaling. |
| 1999 | M | Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor BRU1999 Akt phosphorylates the Forkhead transcription factor FKHRL1 (a FOXO family member), driving its cytoplasmic retention via 14-3-3 binding and blocking Fas-ligand-driven apoptosis — the discovery that placed FOXO transcription factors downstream of Akt/PI3K survival signalling. |