AKT1: A Drug Target / Biomarker (G207)

NCBI ID: G207

AKT1

AKT1: A Drug Target / Biomarker

AKT1, also known as Akt, is a key signaling molecule involved in various cellular processes and has been implicated in cancer progression and metastasis. The activation of AKT1 is crucial for its downstream functions, and dysregulation of AKT1 signaling contributes to the hyperactivation of the pathway in cancer.

There are different mechanisms that can lead to the hyperactivation of the Rac signaling pathway, which is interconnected with AKT1 signaling, in cancer. These mechanisms include reduced degradation via HACE1, altered Rac localization, mutations in Rho GDIs, and oxidation/reduction processes. These abnormalities further contribute to the activation of AKT1.

In terms of AKT1 activation, the distribution of signaling phosphoinositides on endomembranes plays a critical role. The presence of PI(3,4,5)P3 and PI(3,4)P2 on specific membranes indicates potential sites of Akt activity. Additionally, various subcellular compartments contain bona fide Akt substrates that contribute to its biological functions.

Moreover, the activation of AKT1 in the presence of mutant BrafV600E and Cdkn2a loss plays a role in promoting lung and brain metastasis, and this effect is further enhanced by Pten loss. Pten is responsible for converting PIP3 to PIP2, thereby diminishing endogenous AKT1 activation. Conversely, loss of Pten leads to excess PIP3 and hyperactivation of AKT1, resulting in the emergence of lung metastases. Myristoylation of AKT1, which targets it to the plasma membrane, also leads to its activation and promotes metastasis.

Furthermore, AKT1 is involved in macropinocytosis, a process in which certain cup-like structures are formed in macrophages. AKT1 is activated upon the generation of PIP3 in these structures, and this activation is separate from macropinosome formation. PLCgamma and Akt contribute to the closure of the cup structure, which allows the macropinosome to separate from the plasma membrane and move towards the center of the cell.

Finally, the differentiation of human adipose-derived stem cells (hADSCs) is regulated by AKT1. KD025, an inhibitor, suppresses a pro-adipogenic regulator, leading to the inhibition of adipocyte differentiation in hADSCs. This mechanism overcomes the pro-adipogenic activity resulting from Akt activation and ROCK inhibition. In contrast, pan-inhibitors activate Akt and suppress ROCKs, promoting adipogenesis.

In summary, AKT1 plays a critical role in cancer progression and metastasis through its involvement in the Rac signaling pathway. Dysregulation of AKT1 activation can occur through various mechanisms, leading to the hyperactivation of the pathway. AKT1 is also involved in macropinocytosis and the differentiation of hADSCs. Overall, understanding the mechanisms of AKT1 activation and its downstream functions is crucial for developing targeted therapies against cancer and other diseases. .
From the given context information, several viewpoints can be extracted regarding AKT1:

AKT1 is involved in the activation of PI3K/AKT signaling pathways, which affects the expression of cell cycle and apoptosis-related proteins in AML-MDS cells, leading to cell cycle arrest and apoptosis.

Phosphorylation of Ser473 by mTORC2 activates AKT1 by relieving autoinhibition and promoting interactions with other proteins.

Insulin stimulation and oxidative stress can modulate AKT1 activation through redox-dependent mechanisms, such as recruitment to the plasma membrane or inhibitory disulphide formation, respectively.

AKT1 is part of a positive feedback network involving proteins integrin, Paxillin, Rac, PAK, and Merlin, which regulates focal adhesion and cell migration.

AKT1 plays a role in regulating TFEB nuclear translocation and activation. Inhibition of AKT activity promotes TFEB nuclear translocation, leading to enhanced transcriptional regulation of autophagy-lysosome pathways and increased cellular clearance.

Overall, AKT1 is a critical protein involved in various cellular processes, including cell cycle regulation, apoptosis, cell migration, and autophagy-lysosome pathways. Its activation and function can be influenced by phosphorylation, redox-dependent mechanisms, and interactions with other proteins.
Based on the provided context information, the PI3K/AKT/mTOR signaling pathway plays a crucial role in the communication between cancer-associated fibroblasts (CAFs) and cancer cells. The activation of this pathway in CAFs leads to their differentiation and influences various cancer behaviors, particularly cell proliferation .

The mechanism involves the activation of phosphatidylinositol-3-kinase (PI3K), which phosphorylates phosphatidylinositol-4,5-bisphosphate (PIP2) to phosphatidylinositol-3,4,5-trisphosphate (PIP3). miRNA-21 attenuates the inhibition of PTEN on PIP3, allowing PDK1/AKT signaling cascade to be initiated. This cascade ultimately transfers mTOR into the nuclei, regulating gene expression associated with CAF differentiation and motility.

Additionally, the Notch signaling pathway is involved in CAF differentiation through the AKT signaling pathway. B7-H3 promotes AKT phosphorylation, leading to proliferation in CAFs, whereas GW4064 inhibits migration through AKT phosphorylation. Furthermore, CAF-derived factors such as HGF, IGF-2, IL-22, and CXCL5 activate the PI3K/AKT/mTOR axis, while CXCL12 inhibits PTEN. Activation of Smad2/3 by Nodal also induces AKT phosphorylation, and the collaboration of lncRNA UCA1 with mTOR further influences CAF-mediated PI3K/AKT signaling pathway, regulating cell proliferation, migration, and stemness in cancer cells.

Overall, the PI3K/AKT/mTOR signaling pathway is critical for the differentiation of various cells into CAFs and significantly impacts cancer behaviors, particularly cell proliferation. Moreover, the pathway is interconnected with other signaling pathways such as Notch and Nodal, and various factors secreted by CAFs further modulate this signaling axis.

Protein Name: AKT Serine/threonine Kinase 1

Functions: AKT1 is one of 3 closely related serine/threonine-protein kinases (AKT1, AKT2 and AKT3) called the AKT kinase, and which regulate many processes including metabolism, proliferation, cell survival, growth and angiogenesis (PubMed:15861136, PubMed:15526160, PubMed:11882383, PubMed:21620960, PubMed:21432781). This is mediated through serine and/or threonine phosphorylation of a range of downstream substrates (PubMed:15526160, PubMed:11882383, PubMed:21620960, PubMed:21432781). Over 100 substrate candidates have been reported so far, but for most of them, no isoform specificity has been reported (PubMed:15526160, PubMed:11882383, PubMed:21620960, PubMed:21432781). AKT is responsible of the regulation of glucose uptake by mediating insulin-induced translocation of the SLC2A4/GLUT4 glucose transporter to the cell surface (By similarity). Phosphorylation of PTPN1 at 'Ser-50' negatively modulates its phosphatase activity preventing dephosphorylation of the insulin receptor and the attenuation of insulin signaling (By similarity). Phosphorylation of TBC1D4 triggers the binding of this effector to inhibitory 14-3-3 proteins, which is required for insulin-stimulated glucose transport (PubMed:11994271). AKT regulates also the storage of glucose in the form of glycogen by phosphorylating GSK3A at 'Ser-21' and GSK3B at 'Ser-9', resulting in inhibition of its kinase activity (By similarity). Phosphorylation of GSK3 isoforms by AKT is also thought to be one mechanism by which cell proliferation is driven (By similarity). AKT regulates also cell survival via the phosphorylation of MAP3K5 (apoptosis signal-related kinase) (PubMed:11154276). Phosphorylation of 'Ser-83' decreases MAP3K5 kinase activity stimulated by oxidative stress and thereby prevents apoptosis (PubMed:11154276). AKT mediates insulin-stimulated protein synthesis by phosphorylating TSC2 at 'Ser-939' and 'Thr-1462', thereby activating the TORC1 signaling pathway, and leading to both phosphorylation of 4E-BP1 and in activation of RPS6KB1 (PubMed:12150915). Also regulates the TORC1 signaling pathway by catalyzing phosphorylation of CASTOR1 (PubMed:33594058). AKT is involved in the phosphorylation of members of the FOXO factors (Forkhead family of transcription factors), leading to binding of 14-3-3 proteins and cytoplasmic localization (PubMed:10358075). In particular, FOXO1 is phosphorylated at 'Thr-24', 'Ser-256' and 'Ser-319' (PubMed:10358075). FOXO3 and FOXO4 are phosphorylated on equivalent sites (PubMed:10358075). AKT has an important role in the regulation of NF-kappa-B-dependent gene transcription and positively regulates the activity of CREB1 (cyclic AMP (cAMP)-response element binding protein) (PubMed:9829964). The phosphorylation of CREB1 induces the binding of accessory proteins that are necessary for the transcription of pro-survival genes such as BCL2 and MCL1 (PubMed:9829964). AKT phosphorylates 'Ser-454' on ATP citrate lyase (ACLY), thereby potentially regulating ACLY activity and fatty acid synthesis (By similarity). Activates the 3B isoform of cyclic nucleotide phosphodiesterase (PDE3B) via phosphorylation of 'Ser-273', resulting in reduced cyclic AMP levels and inhibition of lipolysis (By similarity). Phosphorylates PIKFYVE on 'Ser-318', which results in increased PI(3)P-5 activity (By similarity). The Rho GTPase-activating protein DLC1 is another substrate and its phosphorylation is implicated in the regulation cell proliferation and cell growth. AKT plays a role as key modulator of the AKT-mTOR signaling pathway controlling the tempo of the process of newborn neurons integration during adult neurogenesis, including correct neuron positioning, dendritic development and synapse formation (By similarity). Signals downstream of phosphatidylinositol 3-kinase (PI(3)K) to mediate the effects of various growth factors such as platelet-derived growth factor (PDGF), epidermal growth factor (EGF), insulin and insulin-like growth factor I (IGF-I) (PubMed:12176338, PubMed:12964941). AKT mediates the antiapoptotic effects of IGF-I (By similarity). Essential for the SPATA13-mediated regulation of cell migration and adhesion assembly and disassembly (PubMed:19934221). May be involved in the regulation of the placental development (By similarity). Phosphorylates STK4/MST1 at 'Thr-120' and 'Thr-387' leading to inhibition of its: kinase activity, nuclear translocation, autophosphorylation and ability to phosphorylate FOXO3 (PubMed:17726016). Phosphorylates STK3/MST2 at 'Thr-117' and 'Thr-384' leading to inhibition of its: cleavage, kinase activity, autophosphorylation at Thr-180, binding to RASSF1 and nuclear translocation (PubMed:20086174, PubMed:20231902). Phosphorylates SRPK2 and enhances its kinase activity towards SRSF2 and ACIN1 and promotes its nuclear translocation (PubMed:19592491). Phosphorylates RAF1 at 'Ser-259' and negatively regulates its activity (PubMed:10576742). Phosphorylation of BAD stimulates its pro-apoptotic activity (PubMed:10926925). P

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•   general information;
•   protein structure and compound binding;
•   protein biological mechanisms;
•   its importance;
•   the target screening and validation;
•   expression level;
•   disease relevance;
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•   related combination drugs;
•   pharmacochemistry experiments;
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•   advantages and risks of development, etc.
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