PI3K-AKT Overview

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The PI3K-AKT signaling pathway is involved in several key steps of the cell cycle1, thus mediating cell growth and proliferation, survival, and metabolism under normal conditions2. This pathway functions downstream of several receptor tyrosine kinases, where phosphorylation of PI3K by the cytoplasmic tyrosine kinase domain of the receptor activates the enzyme3. In fact, initial interest in studying AKT signaling grew because of its mediation of the insulin signaling pathway downstream of the insulin receptor and the insulin-like growth factor I receptor4. At the interior cell membrane, PI3K then phosphorylates the secondary mediator PIP2 to PIP3; PIP3 recruits AKT to the interior cell membrane. Activation of AKT is a multi-step process, whereby AKT undergoes a conformational change to expose a phosphorylation site at threonine 308, which is then phosphorylated by PDK1. A second site on AKT at serine 473 can also be phosphorylated, although the enzyme responsible for this has yet to be elucidated. These activities can be regulated by the activity of PTEN, a 3’-phosphatase that dephosphorylates PI3K and renders it unable to activate AKT3.

Following its activation, AKT translocates from the membrane to the cytosol and nucleus, where it regulates several components of cell cycle progression. AKT is upstream of the mammalian target of rapamycin (mTOR) complexes mTORC1 and mTORC2. Both mTOR complexes are protein kinases that promote cell growth and inhibit autophagy5. mTORC1 is regulated by the tuberous sclerosis complex 1/2, which can be phosphorylated and inactivated by AKT. Interestingly, mTORC2 may function both upstream and downstream of AKT, propagating a positive feedback loop, as it is thought to be one of the kinases capable of phosphorylating serine 473. AKT is also involved in the inhibition of apoptosis by phosphorylating FOXO transcription factors and glycogen synthase kinase 3 (GSK3), which are then inhibited3.

Defects in PI3K-AKT signaling may arise proximal to the receptor or further downstream. Because AKT as a downstream mediator of signaling is ubiquitous and involved in multiple signaling pathways including IGF and EGFR6, dysregulation of AKT leads to disease states. Many cancers are driven by mutations in this pathway, including: gastric cancer7, ovarian cancer8, breast cancer9, kidney cancer10, bladder cancer11, lung cancer12, and others. AKT can mediate primary tumor development13, resistance to chemotherapy14, and dissemination of metastatic disease15. As a result, several therapeutics targeted at inhibiting AKT activity are currently in clinical trials16.

Other diseases reported to have AKT-dependent pathologies include amyotrophic lateral sclerosis17, non-alcoholic fatty liver disease18,19, chronic obstructive pulmonary disease (COPD)20, Alzheimer’s disease21, and Type 2 diabetes22. Therapeutic interventions targeting AKT in some of these diseases are currently being developed in animal models with the goal of increasing AKT activity to prevent tissue damage. In particular, pharmacologic activation of AKT in a murine model of Alzheimer’s disease appeared to improve cognitive function21. In non-alcoholic fatty liver disease, GCSF treatment reduced hepatocyte apoptosis in association with increased PI3K and AKT activity18, and treatment with the antioxidant scutellarin led to improved disease biomarkers correlated with an increase in PI3K-AKT expression levels19.

The PI3K-AKT pathway mediates a multitude of signaling pathways in throughout the body, and plays a role in the pathology of many diseases. To help scientists better understand this pathway in the context of their research, Bethyl manufacturers many antibodies to components of the PI3K-AKT pathway.


Detection of human MEK2 by WB of immunoprecipitates from HeLa lysate

Detection of human MEK2 by WB of immunoprecipitates from HeLa lysate. Antibodies: Rabbit anti-MEK2 (A302-142A and A302-141A). Secondary: ReliaBLOT® reagents (WB120).

Detection of mouse FOXO3a in FFPE renal cell carcinoma by IHC

Detection of mouse FOXO3a in FFPE renal cell carcinoma by IHC. Antibody: Rabbit anti-FOXO3a (IHC-00434). Secondary: HRP-conjugated goat anti-rabbit IgG (A120-501P). Substrate: DAB.

Detection of human PTEN in FFPE breast carcinoma by IHC

Detection of human PTEN in FFPE breast carcinoma by IHC. Antibody: Rabbit anti-PTEN (A300-701A). Secondary: HRP-conjugated goat anti-rabbit IgG (A120-501P). Substrate: DAB.


Below is the entire list of targets involved in PI3K-AKT signaling pathway research. Can’t find what you are looking for? Bethyl offers a custom antibody service.



1. Asnaghi L, Bruno P, Priulla M, Nicolin A. 2004. mTOR: a protein kinase switching between life and death. Pharmacol. Res. Dec;50(6):545–549.

2. Yoon M-S. 2017. The Role of Mammalian Target of Rapamycin (mTOR) in Insulin Signaling. Nutrients Oct 27;9(11):1176.

3. Hers I, Vincent EE, Tavaré JM. 2011. Akt signalling in health and disease. Cell. Signal. Oct;23(10):1515–1527.

4. Nakae J, Park BC, Accili D. 1999. Insulin stimulates phosphorylation of the forkhead transcription factor FKHR on serine 253 through a Wortmannin-sensitive pathway. J. Biol. Chem. Jun 4;274(23):15982–5.

5. Johnson CE, Tee AR. 2017. Exploiting cancer vulnerabilities: mTOR, autophagy, and homeostatic imbalance. Essays Biochem. Dec 12;61(6):699–710.

6. Wee P, Wang Z. 2017. Epidermal Growth Factor Receptor Cell Proliferation Signaling Pathways. Cancers (Basel). May 17;9(5):52.

7. Du D-X, Lian D-B, Amin B-H, Yan W. 2017. Long non-coding RNA CRNDE is a novel tumor promoter by modulating PI3K/AKT signal pathways in human gastric cancer. Eur. Rev. Med. Pharmacol. Sci. Dec;21(23):5392–5398.

8. Kim SI, Lee JW, Lee M, et al. 2017. Genomic landscape of ovarian clear cell carcinoma via whole exome sequencing. Gynecol. Oncol. Dec 9; S0090-8258(17)31552-4.

9. Schettini F, Buono G, Trivedi M V., et al. 2017. PI3K/mTOR Inhibitors in the Treatment of Luminal Breast Cancer. Why, When and to Whom? Breast Care Oct;12(5):290–294.

10. Guo H, German P, Bai S, et al. 2015. The PI3K/AKT Pathway and Renal Cell Carcinoma. J. Genet. Genomics Jul 20;42(7):343–353.

11. Liu ST, Hui G, Mathis C, et al. 2017. The Current Status and Future Role of the Phosphoinositide 3 Kinase/AKT Signaling Pathway in Urothelial Cancer: An Old Pathway in the New Immunotherapy Era. Clin. Genitourin. Cancer Nov 3.

12. Fumarola C, Bonelli MA, Petronini PG, Alfieri RR. 2014. Targeting PI3K/AKT/mTOR pathway in non small cell lung cancer. Biochem. Pharmacol. Aug 1;90(3):197–207.

13. Cameron AJM, Veeriah S, Marshall JJT, et al. 2017. Uncoupling TORC2 from AGC kinases inhibits tumour growth. Oncotarget Aug 9;8(49):84685–84696.

14. Selfe J, Goddard NC, McIntyre A, et al. 2017. IGF1R signalling in testicular germ cell tumour cells impacts on cell survival and acquired cisplatin resistance. J. Pathol. Nov 21.

15. Ji Jo S, Park P, Cha H-R, et al. 2017. Cellular inhibitor of apoptosis protein 2 promotes the epithelial-mesenchymal transition in triple-negative breast cancer cells through activation of the AKT signaling pathway. Oncotarget Aug 12;8(45):78781–78795.

16. Gdowski A, Panchoo M, Treuren T Van, Basu A. 2016. Emerging therapeutics for targeting Akt in cancer. Front. Biosci. (Landmark Ed.) Jan 1;21:757–68.

17. Recabarren-Leiva D, Alarcón M. 2017. New insights into the gene expression associated to amyotrophic lateral sclerosis. Life Sci. Dec 11; S0024-3205(17)30653-7.

18. Nam HH, Jun DW, Jang K, et al. 2017. Granulocyte colony stimulating factor treatment in non-alcoholic fatty liver disease: beyond marrow cell mobilization. Oncotarget Jul 4;8(58):97965–97976.

19. Fan H, Ma X, Lin P, et al. 2017. Scutellarin Prevents Nonalcoholic Fatty Liver Disease (NAFLD) and Hyperlipidemia via PI3K/AKT-Dependent Activation of Nuclear Factor (Erythroid-Derived 2)-Like 2 (Nrf2) in Rats. Med. Sci. Monit. Nov 24;23:5599–5612.

20. Gu W, Yuan Y, Yang H, et al. 2017. Role of miR-195 in cigarette smoke-induced chronic obstructive pulmonary disease. Int. Immunopharmacol. Dec 7;55:49–54.

21. Yi JH, Baek SJ, Heo S, et al. 2018. Direct pharmacological Akt activation rescues Alzheimer’s disease like memory impairments and aberrant synaptic plasticity. Neuropharmacology Jan;128:282–292.

22. Liu S, Li X, Wu Y, et al. 2017. Effects of vaspin on pancreatic β cell secretion via PI3K/Akt and NF-κB signaling pathways. PLoS One Dec 14;12(12):e0189722.