AKT (Protein Kinase B / PKB)

AKT — also called Protein Kinase B (PKB) — is a serine/threonine kinase and the central effector of PI3K signaling. It integrates growth-factor and insulin inputs to drive cell survival, proliferation, glucose uptake, and protein synthesis. In the aging context, AKT sits at the convergence of insulin-igf1 / mtor / ampk signaling: hyper-activation is associated with cancer and metabolic disease, while partial genetic reduction of AKT activity (particularly in invertebrate models) extends lifespan via de-repression of foxo transcription factors.

Identity

UniProt: P31749 (AKT1_HUMAN) — canonical isoform; 480 amino acids
NCBI Gene: 207 (AKT1); HGNC: 391
Gene symbol: AKT1 (HGNC); aliases PKB, PKBα, RAC-PK-alpha
Mouse ortholog: Akt1 (one-to-one; ~98% sequence identity at protein level)
Paralog note: [[akt]] is the canonical AKT1 page. AKT2 and AKT3 are handled as separate entries when seeded; see Paralogs section below.

Paralogs — three mammalian AKT isoforms

Mammals express three closely related AKT paralogs with distinct tissue distributions:

Isoform	Gene	UniProt	Length (aa)	Expression pattern	Aging/metabolic relevance
AKT1 (PKBα)	AKT1	P31749	480	Ubiquitous	Survival/proliferation; role in cellular-senescence via p21/mdm2
AKT2 (PKBβ)	AKT2	P31751	481	High in liver, skeletal muscle, adipose	Primary isoform for insulin-stimulated glut4 translocation / glucose homeostasis
AKT3 (PKBγ)	AKT3	Q9Y243	479	Highest in brain; testis	Neural growth; limited metabolic role

All three share the same domain architecture and dual-phosphorylation activation mechanism (Thr308 equivalent + Ser473 equivalent). Substrate specificity is largely overlapping; isoform differences arise mainly from tissue distribution and subcellular localization.

Domain organization

AKT1 has three principal regions:

Domain	Residues (approx.)	Function
PH domain (Pleckstrin Homology)	1–110	Binds PIP3 (phosphatidylinositol-3,4,5-trisphosphate) at the plasma membrane; required for membrane recruitment and activation
Kinase domain	~150–408	Catalytic; contains activation-loop Thr308
C-terminal regulatory / hydrophobic motif	~409–480	Contains Ser473 in the hydrophobic motif; phosphorylation of Ser473 by mTORC2 stabilizes the active conformation

Activation mechanism — two-step phosphorylation

AKT activation requires sequential events at the plasma membrane ¹ ²:

PI3K generates PIP3. Growth-factor receptor activation (e.g., insulin/IGF-1 → IRS-1/2 → p85/p110 PI3K) converts PIP2 to PIP3 at the inner plasma membrane leaflet. PTEN is the principal PIP3 phosphatase and opposes this step (see pi3k-akt-pathway).
PH domain binds PIP3. The PH domain of cytosolic, inactive AKT binds PIP3 with high affinity, recruiting AKT to the membrane and inducing a conformational change that partially exposes the activation loop.
PDK1 phosphorylates Thr308. 3-phosphoinositide-dependent protein kinase-1 (PDK1), itself recruited to membranes via its own PH domain, phosphorylates AKT at Thr308 in the kinase activation loop ¹. This is required but not sufficient for full activation.
mTORC2 phosphorylates Ser473. The mTOR-containing complex mTORC2 (containing rictor) phosphorylates AKT at Ser473 in the hydrophobic motif ². Full, dual-phosphorylated AKT shows substantially higher kinase activity toward some substrates (e.g., FoxO family members) than Thr308-only phospho-AKT. Sarbassov et al. 2005 demonstrated this by RNA-interference depletion of rictor, which selectively abolished Ser473 phosphorylation while leaving Thr308 intact.
Cytosolic AKT dissociates and phosphorylates substrates throughout the cell.

Deactivation: PP2A and PHLPP phosphatases dephosphorylate Thr308 and Ser473 respectively to return AKT to the basal state.

Consensus substrate motif

AKT preferentially phosphorylates serine or threonine residues in the motif R-X-R-X-X-S/T-Φ (where Φ is a hydrophobic residue), also written as the Basophilic Optimal Motif. The Arg residues at −3 and −5 are critical for recognition.

Key substrates and downstream effects

Substrate	AKT site	Consequence	Aging/pathway link
bad	Ser136	14-3-3 sequestration → BCL-2/BCL-xL freed → survival	Verified on bad (Datta 1997) ³
mdm2	Ser166 / Ser186	Nuclear translocation → p53 ubiquitination → p53 degradation	Reduces p53-driven arrest and senescence ⁴
TSC2 (in tsc1-tsc2)	Thr1462	Inhibits TSC1/2 GAP activity → Rheb-GTP maintained → [[mtor	mTORC1]] active
FoxO1/3/4 (FOXO transcription factors)	Thr32/Ser253 (direct Akt sites on FoxO3a/FKHRL1); Ser315 phosphorylated in cells but not directly by Akt in vitro (indirect, via Akt-activated kinase)	Nuclear export → foxo-target genes repressed (including longevity genes, antioxidants, cell-cycle arrest genes); 14-3-3 binding mediated by pThr32 and pSer253, not pSer315	Core mechanism of IIS longevity extension ⁵
GSK3β	Ser9	Inhibitory phosphorylation → GSK3β inactivated → glycogen synthesis promoted; also reduces tau hyperphosphorylation	Metabolic and neurodegeneration relevance
caspase-9	Ser196	Inhibitory → apoptosis suppressed	Verified on caspase-9 (Cardone 1998; not_oa)
AS160 / TBC1D4	Thr642	Inactivates RAB-GAP → RAB10 active → glut4 vesicle fusion → glucose uptake	Insulin signaling; AKT2-dominant in muscle/fat
eNOS	Ser1177	Activates eNOS → NO production → vascular function	Cardiovascular aging relevance

AKT and the FoxO/longevity axis

The best-characterized longevity-relevant function of AKT is phosphorylation and nuclear exclusion of FoxO (FOXO in vertebrates; DAF-16 in C. elegans) transcription factors ⁵:

Active AKT directly phosphorylates FoxO3a (FKHRL1) at Thr32 and Ser253; these two sites create 14-3-3 binding motifs that retain FoxO in the cytoplasm. Ser315 is also phosphorylated in cells (contributing to the SDS-PAGE mobility shift) but is not directly phosphorylated by Akt in vitro and does not contribute to 14-3-3 binding ⁵.
FoxO exclusion suppresses transcription of stress-resistance and longevity genes (antioxidants, proteostasis factors, cell-cycle inhibitors).
Conversely, reduced IIS signaling (from low insulin/IGF-1 signaling) allows nuclear DAF-16/FoxO accumulation and lifespan extension. In C. elegans, this effect is driven predominantly by SGK-1 loss rather than akt-1/akt-2 reduction per se (see C. elegans lifespan evidence below).

C. elegans lifespan evidence. Hertweck et al. (2004) showed that SGK-1 — not AKT-1 or AKT-2 — is the critical kinase in the worm AKT/PKB complex for control of life span and stress response ⁶. Loss of sgk-1 alone extended mean adult lifespan by ~63% at 25°C (wild-type 14.7±0.3d; sgk-1 24.0±0.4d; p<0.0001; n=147). By contrast, loss of akt-1 alone had no significant effect on longevity (p=0.1642; n=100), and loss of akt-2 alone was also non-significant (p=0.3717; n=101). The akt-1; akt-2 double mutant showed only a weak ~19% extension (p=0.0005; n=132). SGK-1 forms a trimeric complex with AKT-1 and AKT-2 that is phosphorylated by PDK-1; all three kinases can phosphorylate DAF-16 directly. The paper also identifies a second branch of DAF-2 signaling to DAF-16 that is independent of AKT-1/AKT-2/SGK-1. needs-human-replication

Dimension	Status	Notes
Pathway conserved in humans?	yes	IIS → AKT → FoxO axis conserved from worm to human; FOXO3 SNP associated with human longevity
Phenotype conserved in humans?	partial	FOXO3 Thr32 homologous phospho-site confirmed; direct lifespan genetics in humans not testable
Replicated in humans?	in-progress	FOXO3A GG genotype associated with longevity (Willcox 2008 n=615, OR 2.75 — verified on pi3k-akt-pathway); mechanistic link to AKT activity not directly measured in humans

AKT and senescence

AKT activity intersects with cellular-senescence through two opposing routes:

Anti-senescent (survival): AKT phosphorylates MDM2 → p53 degradation → reduced p53-driven senescence induction. AKT also phosphorylates caspase-9 Ser196 (inhibitory), and bad Ser136, broadly suppressing apoptotic/senescent programs.
Pro-senescent (via mTORC1): Sustained AKT → TSC2 inhibition → mTORC1 activation → S6K1 / 4E-BP1 phosphorylation → enhanced protein synthesis and SASP amplification. mTORC1-driven SASP reinforcement is a recognized mechanism in OIS (oncogene-induced senescence) contexts (see mtor, s6k1, sasp). needs-replication for the specific AKT→mTOR→SASP causal chain in human senescent cells.

Cancer context

AKT is one of the most frequently activated oncoproteins in human cancer. Mechanisms include:

PIK3CA gain-of-function mutations (upstream PI3K activation) — in ~30–50% of some cancer types (breast, endometrial, colorectal) per Vasan & Cantley 2022 (verified on pi3k-akt-pathway).
PTEN loss-of-function (opposing phosphatase deleted) — common in glioblastoma, prostate, endometrial cancers.
AKT1 E17K hotspot mutation — constitutively localizes AKT to the membrane independent of PIP3; found in breast, colorectal cancers.
AKT1/2/3 amplification — rarer; reported in gastric, ovarian.

The cancer frequency of PI3K/AKT pathway alterations underscores its centrality to cell survival, but also highlights the challenge of targeting AKT in aging (where partial suppression is desired, not abolition). contradictory-evidence — optimal level of AKT activity for longevity without cancer promotion is not established.

Pharmacology

Three classes of AKT inhibitors have reached clinical development:

Compound	Class	Selectivity	Clinical status (as of 2026)
MK-2206	Allosteric	Pan-AKT	Phase II (multiple cancers); not advanced
Ipatasertib (GDC-0068)	ATP-competitive	Pan-AKT	Phase III (PAKT-B prostate, breast)
Capivasertib (AZD5363)	ATP-competitive	Pan-AKT	FDA-approved 2023 (+ fulvestrant for HR+/HER2− breast cancer with PIK3CA/AKT1/PTEN alteration)

Note: Capivasertib received FDA approval in November 2023 for HR+/HER2− advanced breast cancer in patients with specific PI3K/AKT/PTEN pathway alterations, making it the first approved AKT inhibitor. long-term-unknown — long-term metabolic and aging-related safety of AKT inhibitors in humans (insulin resistance is a known on-target side effect).

Aging-relevant pharmacology note. No clinical program currently targets AKT for longevity or geroprotection. Partial loss-of-function approaches (worm/mouse genetics) cannot be straightforwardly translated to pharmacological AKT inhibition, which produces pan-AKT suppression, metabolic disruption (insulin resistance), and immune effects.

Pathway membership and cross-references

pi3k-akt-pathway — canonical node; AKT is the central effector
insulin-igf1 — upstream signaling cascade
mtor — downstream; AKT → TSC2 → Rheb → mTORC1
ampk — opposing nutrient sensor; AMPK → TSC2 (Thr1271/Ser1387) also inhibits mTORC1; AKT and AMPK act antagonistically on several shared substrates
foxo — key downstream transcription factor family (stub)
dna-damage-response — indirect: AKT phosphorylates MDM2 to suppress p53 under basal conditions; DDR disrupts AKT signaling in some contexts

Limitations and gaps

#gap/needs-human-replication — In C. elegans, lifespan extension via IIS reduction is mediated primarily by SGK-1 loss (not akt-1/akt-2 reduction per se); dAkt reduction in Drosophila is the cleaner AKT-specific invertebrate longevity observation, but no human genetic equivalent exists. FOXO3 longevity SNP is the closest human data.
#gap/needs-canonical-id — AKT2 and AKT3 UniProt IDs (P31751, Q9Y243) are noted in the paralogs table but not independently checked against UniProt for this page.
#gap/dose-response-unclear — Relationship between degree of AKT suppression and aging benefit vs metabolic harm in mammals is poorly characterized; mouse Akt1+/− heterozygotes do not show consistent lifespan extension across strains.
#gap/no-mechanism — How AKT isoform-specific subcellular localization translates into differential substrate phosphorylation in aged vs young cells is not established.
#gap/unsourced — AKT1 E17K hotspot prevalence in cancer; eNOS Ser1177 and GSK3β Ser9 phosphorylation claims need primary-source footnotes.

Footnotes

PMID:8978681 · Alessi et al. 1996 · EMBO J 15:6541 · in-vitro + in-vivo · model: rat adipocytes + Sf9 cells · mechanism of PKB activation by insulin/IGF-1; PDK1 phosphorylation of Thr308 established; no CrossRef DOI available (pre-DOI EMBO era) ↩ ↩²
doi:10.1126/science.1106148 · Sarbassov et al. 2005 · Science · in-vitro (siRNA, HEK293) · mTORC2/rictor phosphorylates AKT Ser473; verified on rictor; archive: not_oa ↩ ↩²
doi:10.1016/s0092-8674(00)80405-5 · Datta et al. 1997 · Cell · n=multiple cell lines · in-vitro · p<0.01 · model: Balb/c 3T3 + HEK293 + COS-7 · AKT phosphorylates BAD Ser136 → 14-3-3 sequestration → survival; verified on bad; archive: downloaded ↩
See pi3k-akt-pathway (verified-partial) — MDM2 Ser166/Ser186 phosphorylation by AKT noted there; primary source verification of this specific claim pending ↩
doi:10.1016/S0092-8674(00)80595-4 · Brunet et al. 1999 · Cell 96:857–868 · in-vitro + transfection · p<0.01 (ANOVA) · model: 293T cells, CCL39 fibroblasts, primary cerebellar granule neurons, Jurkat T cells · Akt directly phosphorylates FKHRL1 (FoxO3a) at Thr32 and Ser253 (confirmed by phospho-specific antibodies and in vitro kinase assay); Ser315 is phosphorylated in cells but not directly by Akt in vitro (indirect, via Akt-activated kinase); pThr32 and pSer253 (not pSer315) create 14-3-3 binding motifs; phosphorylated FKHRL1 is retained in cytoplasm away from Fas ligand gene promoter; survival factor withdrawal → FKHRL1 dephosphorylation, nuclear translocation, Fas ligand induction, apoptosis · archive: downloaded ↩ ↩² ↩³
doi:10.1016/s1534-5807(04)00095-4 · Hertweck, Göbel & Baumeister 2004 · Dev Cell 6:577–588 · n=100–147 per strain · in-vivo · p<0.0001 (sgk-1 vs WT) · model: C. elegans N2 background · SGK-1 is the critical kinase in the AKT-1/AKT-2/SGK-1 trimeric PDK-1 complex for life span and stress resistance; sgk-1 loss alone extends mean lifespan ~63% (14.7→24.0d at 25°C); akt-1 or akt-2 loss alone does NOT significantly extend lifespan; all three kinases phosphorylate DAF-16 directly; a second DAF-2 branch independent of AKT-1/AKT-2/SGK-1 also signals to DAF-16 · archive: downloaded ↩

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