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AKT1

Official Full Name
AKT serine/threonine kinase 1
Organism
Homo sapiens
GeneID
207
Background
This gene encodes one of the three members of the human AKT serine-threonine protein kinase family which are often referred to as protein kinase B alpha, beta, and gamma. These highly similar AKT proteins all have an N-terminal pleckstrin homology domain, a serine/threonine-specific kinase domain and a C-terminal regulatory domain. These proteins are phosphorylated by phosphoinositide 3-kinase (PI3K). AKT/PI3K forms a key component of many signalling pathways that involve the binding of membrane-bound ligands such as receptor tyrosine kinases, G-protein coupled receptors, and integrin-linked kinase. These AKT proteins therefore regulate a wide variety of cellular functions including cell proliferation, survival, metabolism, and angiogenesis in both normal and malignant cells. AKT proteins are recruited to the cell membrane by phosphatidylinositol 3,4,5-trisphosphate (PIP3) after phosphorylation of phosphatidylinositol 4,5-bisphosphate (PIP2) by PI3K. Subsequent phosphorylation of both threonine residue 308 and serine residue 473 is required for full activation of the AKT1 protein encoded by this gene. Phosphorylation of additional residues also occurs, for example, in response to insulin growth factor-1 and epidermal growth factor. Protein phosphatases act as negative regulators of AKT proteins by dephosphorylating AKT or PIP3. The PI3K/AKT signalling pathway is crucial for tumor cell survival. Survival factors can suppress apoptosis in a transcription-independent manner by activating AKT1 which then phosphorylates and inactivates components of the apoptotic machinery. AKT proteins also participate in the mammalian target of rapamycin (mTOR) signalling pathway which controls the assembly of the eukaryotic translation initiation factor 4F (eIF4E) complex and this pathway, in addition to responding to extracellular signals from growth factors and cytokines, is disregulated in many cancers. Mutations in this gene are associated with multiple types of cancer and excessive tissue growth including Proteus syndrome and Cowden syndrome 6, and breast, colorectal, and ovarian cancers. Multiple alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jul 2020]
Synonyms
AKT; PKB; RAC; PRKBA; PKB-ALPHA; RAC-ALPHA;
Bio Chemical Class
mRNA target
Protein Sequence
MSDVAIVKEGWLHKRGEYIKTWRPRYFLLKNDGTFIGYKERPQDVDQREAPLNNFSVAQCQLMKTERPRPNTFIIRCLQWTTVIERTFHVETPEEREEWTTAIQTVADGLKKQEEEEMDFRSGSPSDNSGAEEMEVSLAKPKHRVTMNEFEYLKLLGKGTFGKVILVKEKATGRYYAMKILKKEVIVAKDEVAHTLTENRVLQNSRHPFLTALKYSFQTHDRLCFVMEYANGGELFFHLSRERVFSEDRARFYGAEIVSALDYLHSEKNVVYRDLKLENLMLDKDGHIKITDFGLCKEGIKDGATMKTFCGTPEYLAPEVLEDNDYGRAVDWWGLGVVMYEMMCGRLPFYNQDHEKLFELILMEEIRFPRTLGPEAKSLLSGLLKKDPKQRLGGGSEDAKEIMQHRFFAGIVWQHVYEKKLSPPFKPQVTSETDTRYFDEEFTAQMITITPPDQDDSMECVDSERRPHFPQFSYSASGTA
Open
Approved Drug
1 +
Clinical Trial Drug
13 +
Discontinued Drug
1 +

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Detailed Information

One important molecule takes front stage in the complex network of cellular signaling: AKT1. Key player in the PI3K/AKT/mTOR system, AKT1 is not only a major control of cell survival, proliferation, and metabolism but also a focal point in cancer research and focused treatment. Let's explore this intriguing molecular world and reveal the amazing trip AKT1 takes from its discovery to target for cancer therapy.

Identification and Naming of AKT1

The chronicle of AKT1 begins in 1977 when Dr. Stephen P. Staal of Johns Hopkins University publishes a revolutionary paper in the Proceedings of the National Academy of Sciences (PNAS). From the AKT8 cell line developed from naturally occurring lymphoma in AKR/J mice, he separated the T-8 virus strain. Ten years later, Dr. Staal made yet another discovery when he successfully identified v-akt by cloning the oncogene of the AKT8 virus. He simultaneously found two homologous sequences in human cellular DNA, which he assigned as AKT1 and AKT2. This finding launched more than thirty years of research on the biological roles and processes of AKT1.

Fascinatingly, the name AKT speaks more about its discovery history than with its purpose. "Ak" is the AKR mouse strain, linked to spontaneous thymic lymphomas; "t" is for "thymoma." Consistent with this major chemical family, this name tradition has endured.

AKT1 Molecular Structure and Activation Mechanism

Found on chromosome 14 in the q32.33 region, the human AKT1 gene codes for a 480 amino acid protein with a molecular weight of around 56 kD. Three conserved domains define the AKT1 protein: the C-terminal extension (EXT) including a hydrophobic regulating motif (HM), the N-terminal pleckstrin homology (PH) domain, and the central kinase catalytic (CAT) domain.

AKT1 is inactive and found in the cytoplasm where its PH domain interacts intramolecularly with the CAT domain to generate a "PH-in" conformation, therefore blocking phosphorylation of the activation loop within the kinase domain. Involving a complicated cascade of signaling events, activation of AKT1 may occur at the cell membrane or organelle membranes.

Growth hormones and other stimuli at the cell membrane either G protein-coupled receptors (GPCRs) or receptor tyrosine kinases (RTKs), therefore activating phosphoinositide 3-kinase (PI3K). PIP2 on the inner side of the plasma membrane is phosphorylated by this activation phosphorylates PIP2 producing PIP3. After that, AKT1 moves to the membrane where its PH domain hooks PIP3 to produce a conformational shift known as "PH-out," therefore exposing phosphorylation sites. This pathway causes the T308 site on AKT1 to become phosphorylated, therefore activating the protein.

Crucially, complete AKT1 activation also depends on phosphorylation at the S473 site, a phase regulated by the mTORC2 complex. Phosphatases including PTEN, PP2A, and PHLPP precisely control the deactivation of AKT1 thus maintaining the equilibrium and homeostasis of cellular signaling.

Figure 1 illustrates the downstream substrates phosphorylated by AKT and their roles in regulating various cellular functions, highlighting both activating and inhibitory effects.Figure 1. AKT signaling network (Manning BD et al., 2017)

Diverse Biological Functions of AKT1

AKT1, a multifarious protein kinase, phosphorylates several downstream substrates to control a range of physiological events. Over 100 AKT1 substrates—including elements of cell survival, proliferation, growth, and metabolism—have thus been documented so far.

Regarding cell survival, AKT1 phosphorylates FOXO transcription factors thus enabling their translocation from the nucleus to the cytoplasm, so reducing their pro-apoptotic gene transcription activity. AKT1 may also phosphorylate the Bad protein, therefore disrupting its interaction with Bcl-2 and so stopping death. Moreover, AKT1 turns on IKK, thus activating the NF-κB pathway and so fostering cell survival.

In terms of cell cycle control, AKT1 phosphorylates and reduces the main cell cycle inhibitors p21 and p27 therefore advancing cell cycle development. Also phosphorylates GSK3β, therefore reducing its activity and accumulating β-catenin in the cytoplasm, which then translocates to the nucleus to stimulate gene expression linked with cell division and growth.

By phosphorylating TSC2, AKT1 promotes the mTORC1 signaling pathway in metabolic control, hence fostering protein synthesis and cell growth. Moreover, AKT1 increases glucose intake via translocation of GLUT4 transporters to the cell membrane, therefore influencing glucose metabolism.

AKT1 and cancer

Given AKT1's key involvement in cell survival, proliferation, and metabolism, its aberrant activation has grown to be a major determinant of cancer start and spread. Studies show that elevated AKT1 activity exists in around 40% of breast cancer, ovarian epithelial carcinoma, prostate cancer, and gastric cancer. Usually arising from AKT1 gene mutations and amplifications, this aberrant activation is caused by the most prevalent E17K mutation.

Two important characteristics of AKT1 are changed by the E17K mutation: it promotes AKT1 ubiquitination and binds to the lipid PI (3,4,5), both of which result in improper membrane localization and Thr308 phosphorylation of AKT1, therefore arming cells with aberrant carcinogenic potential. This result offers a necessary theoretical basis for focused anti-tumor treatments aiming to target AKT1.

Targeting AKT1: Difficulties and Possibilities

Targeting AKT1 to block the PI3K/mTOR pathway has long been a priority in the creation of new anti-tumor drugs as AKT1's key role in cancer dictates this. Nonetheless, the participation of AKT1 in many intricate feedback systems poses major difficulties in designing medications with minimal toxicity but great effectiveness.

With multiple potential medications from big pharmaceutical firms failing in the early clinical phases, no AKT1 inhibitors have yet been effectively licensed for usage. Merck's MK-22006, for example, finally failed after more than 40 early studies; Eli Lilly's LY2780301 and Bayer's BAY11259 were also stopped.

Still, as our knowledge of the AKT1 signaling system and its function in tumor resistance grows, new treatment approaches are starting to surface. For instance, endocrine treatment resistance in breast cancer is thought to be developed in great part via the PI3K/AKT pathway. Therefore, co-administering AKT inhibitors to offset the activation of the PI3K/AKT pathway may provide a good strategy to stop the development of resistance in tumor cells.

Future Directions

Though AKT1-targeted treatments present several difficulties, their potential use in cancer therapy is still enormous. As precision medicine develops, tailored therapy plans based on tumor genomic sequencing might open the path for AKT1 inhibitor clinical application. Furthermore, combination therapy approaches—that is, matching AKT1 inhibitors with other targeted drugs or conventional treatments—may result in revolutionary breakthroughs.

References:

  1. Fagerberg L, Hallström BM, Oksvold P, et al. Analysis of the human tissue-specific expression by genome-wide integration of transcriptomics and antibody-based proteomics. Mol Cell Proteomics. 2014;13(2):397-406.
  2. Kumar CC, Madison V. AKT crystal structure and AKT-specific inhibitors. Oncogene. 2005;24(50):7493-7501.
  3. Calleja V, Alcor D, Laguerre M, et al. Intramolecular and intermolecular interactions of protein kinase B define its activation in vivo. PLoS Biol. 2007;5(4):e95.
  4. Manning BD, Toker A. AKT/PKB Signaling: Navigating the Network. Cell. 2017;169(3):381-405.
  5. Liu HW, Bi WT, Huang HT, et al. Satb1 promotes Schwann cell viability and migration via activation of PI3K/AKT pathway. Eur Rev Med Pharmacol Sci. 2018;22(13):4268-4277.
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