General Information of Drug Therapeutic Target (DTT) (ID: TT2MN5K)

DTT Name Phosphorylated protein kinase B (pAKT)
Synonyms RAC-serine/threonine-protein kinase; RAC-PK; Protein kinase B; Protein kinase Akt; PKB
Gene Name AKT1
DTT Type
Clinical trial target
[1]
BioChemical Class
Kinase
UniProt ID
AKT1_HUMAN ; AKT2_HUMAN ; AKT3_HUMAN
TTD ID
T62753
3D Structure
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2D Sequence (FASTA)
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3D Structure (PDB)
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Sequence
MSDVAIVKEGWLHKRGEYIKTWRPRYFLLKNDGTFIGYKERPQDVDQREAPLNNFSVAQC
QLMKTERPRPNTFIIRCLQWTTVIERTFHVETPEEREEWTTAIQTVADGLKKQEEEEMDF
RSGSPSDNSGAEEMEVSLAKPKHRVTMNEFEYLKLLGKGTFGKVILVKEKATGRYYAMKI
LKKEVIVAKDEVAHTLTENRVLQNSRHPFLTALKYSFQTHDRLCFVMEYANGGELFFHLS
RERVFSEDRARFYGAEIVSALDYLHSEKNVVYRDLKLENLMLDKDGHIKITDFGLCKEGI
KDGATMKTFCGTPEYLAPEVLEDNDYGRAVDWWGLGVVMYEMMCGRLPFYNQDHEKLFEL
ILMEEIRFPRTLGPEAKSLLSGLLKKDPKQRLGGGSEDAKEIMQHRFFAGIVWQHVYEKK
LSPPFKPQVTSETDTRYFDEEFTAQMITITPPDQDDSMECVDSERRPHFPQFSYSASGTA
Function
AKT kinases are 3 closely related serine/threonine-protein kinases (AKT1, AKT2 and AKT3), and which regulate many processes including metabolism, proliferation, cell survival, growth and angiogenesis. This is mediated through serine and/or threonine phosphorylation of a range of downstream substrates. Over 100 substrate candidates have been reported so far, but for most of them, no isoform specificity has been reported. AKT is responsible of the regulation of glucose uptake by mediating insulin-induced translocation of the SLC2A4/GLUT4 glucose transporter to the cell surface. Phosphorylation of PTPN1 at 'Ser-50' negatively modulates its phosphatase activity preventing dephosphorylation of the insulin receptor and the attenuation of insulin signaling. Phosphorylation of TBC1D4 triggers the binding of this effector to inhibitory 14-3-3 proteins, which is required for insulin-stimulated glucose transport. 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. Phosphorylation of GSK3 isoforms by AKT is also thought to be one mechanism by which cell proliferation is driven. AKT regulates also cell survival via the phosphorylation of MAP3K5 (apoptosis signal-related kinase). Phosphorylation of 'Ser-83' decreases MAP3K5 kinase activity stimulated by oxidative stress and thereby prevents apoptosis. AKT mediates insulin-stimulated protein synthesis by phosphorylating TSC2 at 'Ser-939' and 'Thr-1462', thereby activating mTORC1 signaling and leading to both phosphorylation of 4E-BP1 and in activation of RPS6KB1. 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. In particular, FOXO1 is phosphorylated at 'Thr-24', 'Ser-256' and 'Ser-319'. FOXO3 and FOXO4 are phosphorylated on equivalent sites. 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). 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. AKT phosphorylates 'Ser-454' on ATP citrate lyase (ACLY), thereby potentially regulating ACLY activity and fatty acid synthesis. Activates the 3B isoform of cyclic nucleotide phosphodiesterase (PDE3B) via phosphorylation of 'Ser-273', resulting in reduced cyclic AMP levels and inhibition of lipolysis. Phosphorylates PIKFYVE on 'Ser-318', which results in increased PI(3)P-5 activity. 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. 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). AKT mediates the antiapoptotic effects of IGF-I. Essential for the SPATA13-mediated regulation of cell migration and adhesion assembly and disassembly. May be involved in the regulation of the placental development. Phosphorylates STK4/MST1 at 'Thr-120' and 'Thr-387' leading to inhibition of its: kinase activity, nuclear translocation, autophosphorylation and ability to phosphorylate FOXO3. 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. Phosphorylates SRPK2 and enhances its kinase activity towards SRSF2 and ACIN1 and promotes its nuclear translocation. Phosphorylates RAF1 at 'Ser-259' and negatively regulates its activity. Phosphorylation of BAD stimulates its pro-apoptotic activity. Phosphorylates KAT6A at 'Thr-369' and this phosphorylation inhibits the interaction of KAT6A with PML and negatively regulates its acetylation activity towards p53/TP53.
KEGG Pathway
EGFR tyrosine kinase inhibitor resistance (hsa01521 )
Endocrine resistance (hsa01522 )
Platinum drug resistance (hsa01524 )
MAPK signaling pathway (hsa04010 )
ErbB signaling pathway (hsa04012 )
Ras signaling pathway (hsa04014 )
Rap1 signaling pathway (hsa04015 )
cGMP-PKG signaling pathway (hsa04022 )
cAMP signaling pathway (hsa04024 )
Chemokine signaling pathway (hsa04062 )
HIF-1 signaling pathway (hsa04066 )
FoxO signaling pathway (hsa04068 )
Sphingolipid signaling pathway (hsa04071 )
Phospholipase D signaling pathway (hsa04072 )
Autophagy - animal (hsa04140 )
mTOR signaling pathway (hsa04150 )
PI3K-Akt signaling pathway (hsa04151 )
AMPK signaling pathway (hsa04152 )
Apoptosis (hsa04210 )
Longevity regulating pathway (hsa04211 )
Longevity regulating pathway - multiple species (hsa04213 )
Cellular senescence (hsa04218 )
Adrenergic signaling in cardiomyocytes (hsa04261 )
VEGF signaling pathway (hsa04370 )
Apelin signaling pathway (hsa04371 )
Osteoclast differentiation (hsa04380 )
Focal adhesion (hsa04510 )
Signaling pathways regulating pluripotency of stem cells (hsa04550 )
Platelet activation (hsa04611 )
Neutrophil extracellular trap formation (hsa04613 )
Toll-like receptor signaling pathway (hsa04620 )
C-type lectin receptor signaling pathway (hsa04625 )
JAK-STAT signaling pathway (hsa04630 )
T cell receptor signaling pathway (hsa04660 )
B cell receptor signaling pathway (hsa04662 )
Fc epsilon RI signaling pathway (hsa04664 )
Fc gamma R-mediated phagocytosis (hsa04666 )
TNF signaling pathway (hsa04668 )
Neurotrophin signaling pathway (hsa04722 )
Cholinergic synapse (hsa04725 )
Dopaminergic synapse (hsa04728 )
Insulin signaling pathway (hsa04910 )
Progesterone-mediated oocyte maturation (hsa04914 )
Estrogen signaling pathway (hsa04915 )
Prolactin signaling pathway (hsa04917 )
Thyroid hormone signaling pathway (hsa04919 )
Adipocytokine signaling pathway (hsa04920 )
Glucagon signaling pathway (hsa04922 )
Regulation of lipolysis in adipocytes (hsa04923 )
Relaxin signaling pathway (hsa04926 )
GnRH secretion (hsa04929 )
Insulin resistance (hsa04931 )
Non-alcoholic fatty liver disease (hsa04932 )
AGE-RAGE signaling pathway in diabetic complications (hsa04933 )
Growth hormone synthesis, secretion and action (hsa04935 )
Alcoholic liver disease (hsa04936 )
Carbohydrate digestion and absorption (hsa04973 )
Alzheimer disease (hsa05010 )
Spinocerebellar ataxia (hsa05017 )
Shigellosis (hsa05131 )
Salmonella infection (hsa05132 )
Yersinia infection (hsa05135 )
Chagas disease (hsa05142 )
Toxoplasmosis (hsa05145 )
Tuberculosis (hsa05152 )
Hepatitis C (hsa05160 )
Hepatitis B (hsa05161 )
Measles (hsa05162 )
Human cytomegalovirus infection (hsa05163 )
Influenza A (hsa05164 )
Human papillomavirus infection (hsa05165 )
Human T-cell leukemia virus 1 infection (hsa05166 )
Kaposi sarcoma-associated herpesvirus infection (hsa05167 )
Herpes simplex virus 1 infection (hsa05168 )
Epstein-Barr virus infection (hsa05169 )
Human immunodeficiency virus 1 infection (hsa05170 )
Pathways in cancer (hsa05200 )
Proteoglycans in cancer (hsa05205 )
Chemical carcinogenesis - receptor activation (hsa05207 )
Chemical carcinogenesis - reactive oxygen species (hsa05208 )
Colorectal cancer (hsa05210 )
Renal cell carcinoma (hsa05211 )
Pancreatic cancer (hsa05212 )
Endometrial cancer (hsa05213 )
Glioma (hsa05214 )
Prostate cancer (hsa05215 )
Melanoma (hsa05218 )
Chronic myeloid leukemia (hsa05220 )
Acute myeloid leukemia (hsa05221 )
Small cell lung cancer (hsa05222 )
Non-small cell lung cancer (hsa05223 )
Breast cancer (hsa05224 )
Hepatocellular carcinoma (hsa05225 )
Gastric cancer (hsa05226 )
Central carbon metabolism in cancer (hsa05230 )
Choline metabolism in cancer (hsa05231 )
PD-L1 expression and PD-1 checkpoint pathway in cancer (hsa05235 )
Diabetic cardiomyopathy (hsa05415 )
Lipid and atherosclerosis (hsa05417 )
Fluid shear stress and atherosclerosis (hsa05418 )
Reactome Pathway
PIP3 activates AKT signaling (R-HSA-1257604 )
Downregulation of ERBB2 (R-HSA-1358803 )
Translocation of SLC2A4 (GLUT4) to the plasma membrane (R-HSA-1445148 )
Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation (R-HSA-1474151 )
MTOR signalling (R-HSA-165159 )
AKT phosphorylates targets in the cytosol (R-HSA-198323 )
AKT phosphorylates targets in the nucleus (R-HSA-198693 )
Negative regulation of the PI3K/AKT network (R-HSA-199418 )
eNOS activation (R-HSA-203615 )
AKT-mediated inactivation of FOXO1A (R-HSA-211163 )
Integrin signaling (R-HSA-354192 )
Deactivation of the beta-catenin transactivating complex (R-HSA-3769402 )
CD28 dependent PI3K/Akt signaling (R-HSA-389357 )
CTLA4 inhibitory signaling (R-HSA-389513 )
G beta (R-HSA-392451 )
Butyrate Response Factor 1 (BRF1) binds and destabilizes mRNA (R-HSA-450385 )
KSRP (KHSRP) binds and destabilizes mRNA (R-HSA-450604 )
VEGFR2 mediated vascular permeability (R-HSA-5218920 )
TP53 Regulates Metabolic Genes (R-HSA-5628897 )
Constitutive Signaling by AKT1 E17K in Cancer (R-HSA-5674400 )
Interleukin-4 and Interleukin-13 signaling (R-HSA-6785807 )
Regulation of TP53 Degradation (R-HSA-6804757 )
Regulation of TP53 Activity through Acetylation (R-HSA-6804758 )
Regulation of TP53 Activity through Association with Co-factors (R-HSA-6804759 )
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling (R-HSA-6811558 )
Cyclin E associated events during G1/S transition (R-HSA-69202 )
Cyclin A (R-HSA-69656 )
PTK6 Regulates RTKs and Their Effectors AKT1 and DOK1 (R-HSA-8849469 )
RAB GEFs exchange GTP for GDP on RABs (R-HSA-8876198 )
RUNX2 regulates genes involved in cell migration (R-HSA-8941332 )
Regulation of PTEN stability and activity (R-HSA-8948751 )
Extra-nuclear estrogen signaling (R-HSA-9009391 )
Negative regulation of NOTCH4 signaling (R-HSA-9604323 )
FLT3 Signaling (R-HSA-9607240 )
Regulation of localization of FOXO transcription factors (R-HSA-9614399 )
Estrogen-dependent nuclear events downstream of ESR-membrane signaling (R-HSA-9634638 )
KEAP1-NFE2L2 pathway (R-HSA-9755511 )
SARS-CoV-2 targets host intracellular signalling and regulatory pathways (R-HSA-9755779 )
Activation of BAD and translocation to mitochondria (R-HSA-111447 )

Molecular Interaction Atlas (MIA) of This DTT

Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DTT
1 Clinical Trial Drug(s) Targeting This DTT
Drug Name Drug ID Indication ICD 11 Highest Status REF
MNX-100 DMQA3MV Medulloblastoma 2A00.10 Phase 2 [1]
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References

1 Clinical pipeline report, company report or official report of MetronomX.