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PI3K-Akt Signaling

Written/Edited by Dr. Stefan Pellenz, PhD

The PI3K/Akt pathway is pivotal for cellular homeostasis, neurological development, metabolism, and other processes. It regulates various aspects of cellular development such as apoptosis, cell cycle progression, and cell differentiation.

The key regulator of the PI3K/Akt pathway is Akt/PKB, a family of three closely related serine/threonine-protein kinases. Akt1/PKB alpha plays an important role in cell proliferation and cell metabolism. Akt2/PKB beta is of great significance for glucose metabolism. Akt3/PKB gamma is the least characterized member of the Akt family but it is mainly expressed in the brain where it is thought to regulate mitochondrial biogenesis.

Loss of function of the major Akt regulators PI3K and PTEN can lead to hyperactivation of Akt. PI3Ks are an enzyme family that phosphorylate PtdIns (Phosphatidylinositol) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3). Upon activation by receptor tyrosine kinase PI3K phosphorylates PIP2 to PIP3 which then activates Akt signaling. PTEN acts as a negative regulator of the signal transduction by dephosphorylation of PIP3 to PIP2.

Among the primary targets of AKT are mTORC1, which promotes protein synthesis and cell growth, and GSK3β, whose inhibition enhances glycogen synthesis and prevents apoptosis. Additionally, AKT phosphorylates and inactivates pro-apoptotic proteins such as BAD and FOXO transcription factors, thereby enhancing cell survival. Conversely, it activates MDM2, leading to the degradation of p53 and further promoting cell survival. The inhibition of TSC2 by AKT relieves its suppression on mTORC1, further stimulating anabolic processes.

Mutations in Akt contribute oftentimes to deregulation of these processes and the emergence of various forms of cancer. Akt hyperactivation also leads to increased glycolysis, thus supporting the metabolic transformation of cancer cells. Akt has been implicated in the development of cancer drug resistance and is therefore subject of preclinical and clinical research. However, Akt activation alone is usually not sufficient and other mutations are generally necessary to create the cancer phenotype.

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Related Pathways and Resources

References:

Xie, Shi, Sheng, Han, Li, Zhao, Jiang, Feng, Li, Gu: "PI3K/Akt signaling transduction pathway, erythropoiesis and glycolysis in hypoxia (Review)." in: Molecular medicine reports, Vol. 19, Issue 2, pp. 783-791, (2019) (PubMed).
Karar, Maity: "PI3K/AKT/mTOR Pathway in Angiogenesis." in: Frontiers in molecular neuroscience, Vol. 4, pp. 51, (2012) (PubMed).
Kma, Baruah: "The interplay of ROS and the PI3K/Akt pathway in autophagy regulation." in: Biotechnology and applied biochemistry, Vol. 69, Issue 1, pp. 248-264, (2022) (PubMed).
Rascio, Spadaccino, Rocchetti, Castellano, Stallone, Netti, Ranieri: "The Pathogenic Role of PI3K/AKT Pathway in Cancer Onset and Drug Resistance: An Updated Review." in: Cancers, Vol. 13, Issue 16, (2021) (PubMed).
Hennessy, Smith, Ram, Lu, Mills: "Exploiting the PI3K/AKT pathway for cancer drug discovery." in: Nature reviews. Drug discovery, Vol. 4, Issue 12, pp. 988-1004, (2006) (PubMed).

Akt

AKT1 (V-Akt Murine Thymoma Viral Oncogene Homolog 1):

AKT2 (V-Akt Murine Thymoma Viral Oncogene Homolog 2):

AKT3 (V-Akt Murine Thymoma Viral Oncogene Homolog 3 (Protein Kinase B, Gamma)):

AMPA receptors

GLUR1 - Glutamate Receptor 1:

GRIA2 (Glutamate Receptor, Ionotropic, AMPA 2):

GRIA3 - Glutamate Receptor 3:

GRIA4 (Glutamate Receptor, Ionotropic, AMPA 4):

Apoptosis

BCL2 - Bcl-2:

MDM2 (Mdm2, p53 E3 Ubiquitin Protein Ligase Homolog (Mouse)):

BAD (BCL2-Associated Agonist of Cell Death):

BAX (BCL2-Associated X Protein):

BCL2L11 - BIM:

FOXO1 (Forkhead Box O1):

TP53 - p53:

Cell cycle

CCNA2 - Cyclin A:

CDKN1A - p21:

CCND1 - Cyclin D1:

CDK2 (Cyclin-Dependent Kinase 2):

CDK2AP2 (Cyclin-Dependent Kinase 2 Associated Protein 2):

GSK3a - GSK3 alpha:

Cell survival

EIF4EBP1 - eIF4EBP1:

RPS6KB1 (Ribosomal Protein S6 Kinase, 70kDa, Polypeptide 1):

ATG13 (Autophagy Related 13):

RPS6KB2 (Ribosomal Protein S6 Kinase, 70kDa, Polypeptide 2):

Glucose metabolism

GYS1 - Glycogen Synthase 1:

PIP5K1B (Phosphatidylinositol-4-Phosphate 5-Kinase, Type I, beta):

PFKFB2 (6-phosphofructo-2-Kinase/fructose-2,6-Biphosphatase 2):

GSK3a - GSK3 alpha:

HK2 - Hexokinase 2:

PIP5K1A (Phosphatidylinositol-4-Phosphate 5-Kinase, Type I, alpha):

PIP5K1C (Phosphatidylinositol-4-Phosphate 5-Kinase, Type I, gamma):

Immune response

GSK3a - GSK3 alpha:

NCF1 (Neutrophil Cytosol Factor 1):

CHUK - IKK alpha:

MAP3K8 (Mitogen-Activated Protein Kinase Kinase Kinase 8):

mTORC1

GBL (G protein beta subunit-like):

RPTOR - Raptor:

DEPTOR (DEP Domain Containing mTOR-Interacting Protein):

mTOR - MTOR:

mTORC2

DEPTOR (DEP Domain Containing mTOR-Interacting Protein):

TNPO1 - Transportin 1:

mTOR - MTOR:

MAPKAP1 (Mitogen-Activated Protein Kinase Associated Protein 1):

GBL (G protein beta subunit-like):

PRR5 (Proline Rich 5 (Renal)):

Neural development

HTT - Huntingtin:

PDK

PDPK1 (3-phosphoinositide Dependent Protein Kinase-1):

PDK1 (Pyruvate Dehydrogenase Kinase 1):

PDK2 (Pyruvate Dehydrogenase Kinase, Isozyme 2):

PDK3 (Pyruvate Dehydrogenase Kinase, Isozyme 3):

PDK4 (Pyruvate Dehydrogenase Kinase, Isozyme 4):

PHLPP

PHLPP1 (PH Domain and Leucine Rich Repeat Protein Phosphatase 1):

PHLPP1 Antibodies

PHLPP2 (PH Domain and Leucine Rich Repeat Protein Phosphatase 2):

PI3K

PIK3CA (Phosphoinositide-3-Kinase, Catalytic, alpha Polypeptide):

PIK3R5 (Phosphoinositide-3-Kinase, Regulatory Subunit 5):

PIK3CG - PIK3 gamma:

PIK3R6 (Phosphoinositide-3-Kinase, Regulatory Subunit 6):

PIK3R5 (Phosphoinositide-3-Kinase, Regulatory Subunit 5):

PP2A

PPP2CA (Protein Phosphatase 2, Catalytic Subunit, alpha Isozyme):

PPP2R4 (Protein Phosphatase 2A Activator, Regulatory Subunit 4):

MTS - Microtubule Star:

Microtubule Star Antibodies

PPP2R1A (Protein Phosphatase 2, Regulatory Subunit A, alpha):

PPP2R1B (Protein Phosphatase 2, Regulatory Subunit A, beta):

PPP2R3A (Protein Phosphatase 2, Regulatory Subunit B'', alpha):

PPP2R3A Antibodies

PPP2R3C (Protein Phosphatase 2, Regulatory Subunit B'', gamma):

PPP2R5A (Protein Phosphatase 2, Regulatory Subunit B' alpha):

PPP2R5B (Protein Phosphatase 2, Regulatory Subunit B', beta):

PPP2R5D (Protein Phosphatase 2, Regulatory Subunit B', delta):

PPP2R5E (Protein Phosphatase 2, Regulatory Subunit B', epsilon Isoform):

PPP2R5C (Protein Phosphatase 2, Regulatory Subunit B', gamma):

PPP2R2B (Protein Phosphatase 2, Regulatory Subunit B, beta):

PPP2R2C (Protein Phosphatase 2, Regulatory Subunit B, gamma):

PPP2R3B (Protein Phosphatase 2A 48 KDa Regulatory Subunit):

Others

HBXIP (Hepatitis B Virus X-Interacting Protein):

LAMTOR2 (Late Endosomal/lysosomal Adaptor, MAPK and mTOR Activator 2):

MAPKSP1 (Mitogen-Activated Protein Kinase Kinase 1 Interacting Protein 1):

PITRM1 (Pitrilysin Metallopeptidase 1):

PPP1R2 (Protein Phosphatase 1, Regulatory (Inhibitor) Subunit 2):

PPP1R2 Antibodies

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