Protein kinase B (PKB)

Overview

Protein kinase B (PKB), also known as AKT, is a serine/threonine kinase and the central effector of the phosphoinositide 3-kinase (PI3K)/AKT/mTOR pathway. Activation is a two-step, membrane-dependent event: PI3K generates PIP3, which recruits PKB through its pleckstrin homology domain, whereupon PDK1 phosphorylates Thr308 in the activation loop and mTORC2 phosphorylates Ser473 to complete activation. The phosphatase PTEN opposes the first step by removing the 3-phosphate from PIP3, and its loss leaves the kinase constitutively active. Once active, PKB phosphorylates substrates governing survival, proliferation, growth and metabolism — glycogen synthase kinase 3β (GSK-3β), FOXO transcription factors, the pro-apoptotic protein BAD, and the TSC complex upstream of the mechanistic target of rapamycin (mTOR). Humans express three isoforms with distinct emphases rather than interchangeable roles: AKT1 in growth and survival, AKT2 in insulin-responsive glucose uptake in muscle and fat, and AKT3 predominantly in brain. Because its phosphorylation state reports on PI3K pathway activity downstream of multiple inputs — signaling through the epidermal growth factor receptor (EGFR), fibroblast growth factor receptors and other receptor tyrosine kinases — phosphorylated AKT (p-AKT) is among the most commonly used readouts of pathway activation in biomedical research.

The axis is one of the most frequently deregulated in human cancer, usually through PIK3CA mutation or PTEN loss rather than through AKT itself, though the recurrent AKT1 E17K substitution activates the kinase directly by driving membrane localization. Work in hepatocellular carcinoma and breast cancer implicates PTEN/AKT and p53-linked signaling in proliferation, cell-cycle progression and chemotherapy resistance, and the pathway's crosstalk with MYC and NF-κB ties it to transcriptional and inflammatory programs. ATP-competitive and allosteric AKT inhibitors have reached the clinic, with targeted degraders in development; because the same kinase carries insulin's signal, hyperglycemia is a mechanism-based class toxicity rather than an incidental one.

Beyond oncology, PKB underlies insulin-responsive glucose and lipid handling and is examined in obesity, type 2 diabetes, sepsis-associated liver injury and metabolic dysfunction–associated steatotic liver disease, often alongside AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptors. AKT/GSK-3β signaling is studied in neurodegeneration, where it regulates tau phosphorylation and neuronal apoptosis, and pathway activation contributes to angiogenesis, epithelial–mesenchymal transition and tissue repair including skin wound healing. AKT1 recurs as a hub in network-pharmacology analyses of natural products such as quercetin and kaempferol, a literature whose in vivo relevance is largely unsettled.

Recent Publications Summary (latest 30 papers)

Recent studies continued to position Protein kinase B (PKB/Akt) as a central signaling node in diverse disease models, especially in cancer, metabolic disease, inflammation, and tissue repair. In several network pharmacology and experimental studies, Akt1 or AKT-related pathways were identified as key targets for natural products and herbal formulations, including quercetin from Cyathulae Radix in osteoporosis, Cistanoside A in Alzheimer’s disease models, paeonol in intrauterine adhesion, Scutellaria baicalensis in polycystic ovary syndrome, Persicaria lapathifolia leaf extract in diabetes, and Jinshanxiaoke granules in metabolic dysfunction–associated steatotic liver disease 42474720Jul42423799Jul42062178Apr42294648Jun41990533Apr41990925Apr. These studies generally linked Akt signaling to antioxidant, anti-inflammatory, pro-osteogenic, or metabolic effects, with outcomes assessed using cell viability assays, oxidative stress readouts, histology, and pathway-focused western blotting or docking analyses 42474720Jul42423799Jul42062178Apr42294648Jun41990533Apr41990925Apr.

In oncology, PKB/Akt remained a frequent mechanistic focus for tumor growth, resistance, and immune modulation. Exosomal transfer of phosphorylated AKT was reported to drive doxorubicin resistance in breast cancer 42417926Jul, while CNOT9 promoted hepatocellular carcinoma proliferation and cell-cycle progression through the PTEN/AKT/p53 axis 42384246Jul. PRXL2B was shown to enhance hepatocellular carcinoma progression and reduce the efficacy of oncolytic adenovirus H101 by suppressing AKT phosphorylation and PD-L1 expression 42161529May. Additional studies linked AKT signaling to gefitinib resistance in lung adenocarcinoma via CAMK2D isoform 15 42152470May, to metastatic castration-resistant prostate cancer through dual BRD4/AKT inhibition 41966583Apr, and to broad anticancer activity of a nutraceutical formulation (Vernolac) in which AKT1 emerged as a hub target 42384725Jul. A separate drug-design platform, RIMTAC, also used AKT as a proof-of-concept degradation target, demonstrating that indirect VHL recruitment via RIPK1 could induce AKT degradation 42417401Jul.

Beyond cancer, Akt was repeatedly implicated in inflammatory, neurological, and regenerative contexts. Dimethyl fumarate improved post-infarct myocardial injury in rats and was associated with modulation of the NRG-1/ErbB2/Akt pathway and reduced oxidative stress 42229738Jun. Ergothioneine protected against experimental ischemic stroke through activation of the PI3K/Akt/Nrf2 pathway 42214028May, and electroacupuncture alleviated depressive-like behaviors in chronic stress rats by enhancing autophagy and attenuating hippocampal neuroinflammation via the VEGF/AKT1/ERK pathway 42149321May. In spinal cord injury, PRP-primed bone marrow mesenchymal stem cell-derived exosomes acted through the miR-29a-3p/PTEN/PI3K/Akt/mTOR axis to inhibit neuronal apoptosis and autophagy and promote nerve regeneration 42165939May. Butyrate was also investigated in blood–brain barrier models, where insulin signaling and AKT-related mechanisms were examined in relation to amyloid-beta transport and endothelial accumulation in Alzheimer’s disease 42166642May.

Several studies further highlighted AKT as a mediator of cell survival, autophagy, and fibrotic or immune responses. Masitinib was reported to paradoxically induce AKT phosphorylation through a VPS34- and rapamycin-sensitive pathway while altering lysosomal function and autophagic flux 42009094Apr. In pulmonary fibrosis, CHI3L1 enhanced TGF-β1 signaling through SMAD, AKT, and ERK pathways, and combined anti-CHI3L1/anti-PD-1 therapy showed greater antifibrotic efficacy than monotherapy 42048160Apr. In gastric cancer, lenvatinib combined with pembrolizumab was associated with changes in immunosuppressive macrophages and response to PD-1 blockade, fitting broader interest in multikinase inhibition and immune modulation where AKT-related signaling is often relevant 42044259Apr. Collectively, these publications reinforce PKB/Akt as a versatile therapeutic target and signaling hub across disease systems, with most studies using pathway validation, functional assays, and in vivo models to connect Akt modulation to changes in proliferation, apoptosis, oxidative stress, inflammation, autophagy, or treatment response 42417926Jul42384246Jul42161529May42152470May41966583Apr42229738Jun42214028May42165939May42166642May42009094Apr42048160Apr42044259Apr.

What Changes, What Holds

1. Akt remains a broadly reused signaling node, but these studies mostly extend its known disease breadth rather than changing its core biology
REINFORCES The new work keeps PKB/Akt in the same role the Overview assigns it: a central pathway readout and intervention point across cancer, metabolic disease, inflammation, and repair. What changes is mainly the catalog of contexts and natural-product leads, not the mechanism itself. The evidence is largely preclinical and pathway-focused, so it sharpens the sense that Akt is a recurring downstream effector, but it does not displace the established PI3K/PIP3/PTEN framework 42474720Jul42423799Jul.

2. Akt-linked resistance and tumor progression remain consistent with the established cancer model, while degradation strategies add a therapeutic twist
REINFORCES Exosomal p-AKT in breast cancer, PTEN/AKT/p53 involvement in hepatocellular carcinoma, and AKT-associated resistance or immune effects in other tumors all fit the Overview’s account of PI3K/AKT as a major oncogenic and resistance axis. The added wrinkle is that one platform now treats AKT itself as a degradable target, but that is an extension of therapeutic strategy, not a new biological role. These are mechanistically coherent, mostly preclinical findings that strengthen the case for AKT as a cancer endpoint 42417926Jul42384246Jul.

3. Akt continues to look like a shared survival and repair mediator outside cancer, with no challenge to the baseline mechanism
REINFORCES The new studies place Akt in myocardial injury, stroke, depression-related neuroinflammation, spinal cord repair, and blood-brain barrier biology, which broadens the disease map but does not contradict the Overview’s description of Akt in survival, apoptosis control, and tissue repair. The work is mostly associative or pathway-validated, so it supports Akt as a common downstream node in stress responses rather than redefining its function. Any disease-specific claims remain unsettled until stronger causal evidence is available 42229738Jun42165939May.

4. Akt is still being used as a readout of survival, autophagy, and fibrotic signaling, but the direction of regulation can be context-dependent
REINFORCES The new papers reinforce the Overview’s view of Akt as a mediator of cell survival, autophagy, inflammation, and fibrosis, while also showing that some agents can increase Akt phosphorylation as part of an unexpected lysosomal or autophagic response. That does not overturn the baseline; it highlights that p-Akt is not uniformly a marker of benefit or inhibition and must be interpreted in pathway context. The evidence is preclinical and mechanistic, so the main update is about nuance, not replacement 42009094Apr42048160Apr.