Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTBB632K)

DOT Name	RAC-beta serine/threonine-protein kinase (AKT2)
Synonyms	EC 2.7.11.1; Protein kinase Akt-2; Protein kinase B beta; PKB beta; RAC-PK-beta
Gene Name	AKT2
Related Disease	Hypoinsulinemic hypoglycemia and body hemihypertrophy ( ) Obsolete diabetes mellitus, noninsulin-dependent ( ) AKT2-related familial partial lipodystrophy ( ) Non-insulin dependent diabetes ( )
UniProt ID	AKT2_HUMAN
3D Structure	Download 2D Sequence (FASTA) Download 3D Structure (PDB) Download
PDB ID	1GZK; 1GZN; 1GZO; 1MRV; 1MRY; 1O6K; 1O6L; 1P6S; 2JDO; 2JDR; 2UW9; 2X39; 2XH5; 3D0E; 3E87; 3E88; 3E8D; 8Q61
EC Number	2.7.11.1
Pfam ID	PF00169 ; PF00069 ; PF00433
Sequence	MNEVSVIKEGWLHKRGEYIKTWRPRYFLLKSDGSFIGYKERPEAPDQTLPPLNNFSVAEC QLMKTERPRPNTFVIRCLQWTTVIERTFHVDSPDEREEWMRAIQMVANSLKQRAPGEDPM DYKCGSPSDSSTTEEMEVAVSKARAKVTMNDFDYLKLLGKGTFGKVILVREKATGRYYAM KILRKEVIIAKDEVAHTVTESRVLQNTRHPFLTALKYAFQTHDRLCFVMEYANGGELFFH LSRERVFTEERARFYGAEIVSALEYLHSRDVVYRDIKLENLMLDKDGHIKITDFGLCKEG ISDGATMKTFCGTPEYLAPEVLEDNDYGRAVDWWGLGVVMYEMMCGRLPFYNQDHERLFE LILMEEIRFPRTLSPEAKSLLAGLLKKDPKQRLGGGPSDAKEVMEHRFFLSINWQDVVQK KLLPPFKPQVTSEVDTRYFDDEFTAQSITITPPDRYDSLGLLELDQRTHFPQFSYSASIR E
Function	AKT2 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. 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. Involved in the inhibition of ciliogenesis associated with RAB8-dependent cilia growth ; One of the few specific substrates of AKT2 identified recently is PITX2. Phosphorylation of PITX2 impairs its association with the CCND1 mRNA-stabilizing complex thus shortening the half-life of CCND1. AKT2 seems also to be the principal isoform responsible of the regulation of glucose uptake. Phosphorylates C2CD5 on 'Ser-197' during insulin-stimulated adipocytes. AKT2 is also specifically involved in skeletal muscle differentiation, one of its substrates in this process being ANKRD2. Down-regulation by RNA interference reduces the expression of the phosphorylated form of BAD, resulting in the induction of caspase-dependent apoptosis. Phosphorylates CLK2 on 'Thr-343'.
Tissue Specificity	Expressed in all cell types so far analyzed.
KEGG Pathway	EGFR tyrosine ki.se inhibitor resistance (hsa01521 ) Endocrine resistance (hsa01522 ) Platinum drug resistance (hsa01524 ) MAPK sig.ling pathway (hsa04010 ) ErbB sig.ling pathway (hsa04012 ) Ras sig.ling pathway (hsa04014 ) Rap1 sig.ling pathway (hsa04015 ) cGMP-PKG sig.ling pathway (hsa04022 ) cAMP sig.ling pathway (hsa04024 ) Chemokine sig.ling pathway (hsa04062 ) HIF-1 sig.ling pathway (hsa04066 ) FoxO sig.ling pathway (hsa04068 ) Sphingolipid sig.ling pathway (hsa04071 ) Phospholipase D sig.ling pathway (hsa04072 ) Autophagy - animal (hsa04140 ) mTOR sig.ling pathway (hsa04150 ) PI3K-Akt sig.ling pathway (hsa04151 ) AMPK sig.ling pathway (hsa04152 ) Apoptosis (hsa04210 ) Longevity regulating pathway (hsa04211 ) Longevity regulating pathway - multiple species (hsa04213 ) Cellular senescence (hsa04218 ) Adrenergic sig.ling in cardiomyocytes (hsa04261 ) VEGF sig.ling pathway (hsa04370 ) Apelin sig.ling pathway (hsa04371 ) Osteoclast differentiation (hsa04380 ) Focal adhesion (hsa04510 ) Sig.ling pathways regulating pluripotency of stem cells (hsa04550 ) Platelet activation (hsa04611 ) Neutrophil extracellular trap formation (hsa04613 ) Toll-like receptor sig.ling pathway (hsa04620 ) C-type lectin receptor sig.ling pathway (hsa04625 ) JAK-STAT sig.ling pathway (hsa04630 ) T cell receptor sig.ling pathway (hsa04660 ) B cell receptor sig.ling pathway (hsa04662 ) Fc epsilon RI sig.ling pathway (hsa04664 ) Fc gamma R-mediated phagocytosis (hsa04666 ) TNF sig.ling pathway (hsa04668 ) Neurotrophin sig.ling pathway (hsa04722 ) Cholinergic sy.pse (hsa04725 ) Dopaminergic sy.pse (hsa04728 ) Regulation of actin cytoskeleton (hsa04810 ) Insulin sig.ling pathway (hsa04910 ) Progesterone-mediated oocyte maturation (hsa04914 ) Estrogen sig.ling pathway (hsa04915 ) Prolactin sig.ling pathway (hsa04917 ) Thyroid hormone sig.ling pathway (hsa04919 ) Adipocytokine sig.ling pathway (hsa04920 ) Glucagon sig.ling pathway (hsa04922 ) Regulation of lipolysis in adipocytes (hsa04923 ) Relaxin sig.ling pathway (hsa04926 ) GnRH secretion (hsa04929 ) Insulin resistance (hsa04931 ) Non-alcoholic fatty liver disease (hsa04932 ) AGE-RAGE sig.ling 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 ) Re.l 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 ) Activation of AKT2 (R-HSA-165158 ) PDE3B signalling (R-HSA-165160 ) Inhibition of TSC complex formation by PKB (R-HSA-165181 ) 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 ) AKT-mediated inactivation of FOXO1A (R-HSA-211163 ) 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 ) VEGFR2 mediated vascular permeability (R-HSA-5218920 ) TP53 Regulates Metabolic Genes (R-HSA-5628897 ) Constitutive Signaling by AKT1 E17K in Cancer (R-HSA-5674400 ) 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 ) Cyclin E associated events during G1/S transition (R-HSA-69202 ) Cyclin A (R-HSA-69656 ) 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 ) 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 DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance
Hypoinsulinemic hypoglycemia and body hemihypertrophy	DISZ33Q6	Definitive	Autosomal dominant	[1]
Obsolete diabetes mellitus, noninsulin-dependent	DISS46MZ	Strong	Autosomal dominant	[2]
AKT2-related familial partial lipodystrophy	DISS4DRQ	Supportive	Autosomal dominant	[3]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Autosomal dominant	[4]
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Molecular Interaction Atlas (MIA)

MIA Detail

Jump to Detail Molecular Interaction Atlas of This DOT

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic trioxide	DM61TA4	Approved	RAC-beta serine/threonine-protein kinase (AKT2) decreases the response to substance of Arsenic trioxide.	[33]
Afimoxifene	DMFORDT	Phase 2	RAC-beta serine/threonine-protein kinase (AKT2) decreases the response to substance of Afimoxifene.	[34]
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24 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of RAC-beta serine/threonine-protein kinase (AKT2).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of RAC-beta serine/threonine-protein kinase (AKT2).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of RAC-beta serine/threonine-protein kinase (AKT2).	[7]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of RAC-beta serine/threonine-protein kinase (AKT2).	[8]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of RAC-beta serine/threonine-protein kinase (AKT2).	[9]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of RAC-beta serine/threonine-protein kinase (AKT2).	[10]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of RAC-beta serine/threonine-protein kinase (AKT2).	[11]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the expression of RAC-beta serine/threonine-protein kinase (AKT2).	[7]
Aspirin	DM672AH	Approved	Aspirin increases the expression of RAC-beta serine/threonine-protein kinase (AKT2).	[12]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of RAC-beta serine/threonine-protein kinase (AKT2).	[11]
DTI-015	DMXZRW0	Approved	DTI-015 decreases the expression of RAC-beta serine/threonine-protein kinase (AKT2).	[14]
Menthol	DMG2KW7	Approved	Menthol decreases the expression of RAC-beta serine/threonine-protein kinase (AKT2).	[15]
Obeticholic acid	DM3Q1SM	Approved	Obeticholic acid decreases the expression of RAC-beta serine/threonine-protein kinase (AKT2).	[16]
Sulindac	DM2QHZU	Approved	Sulindac decreases the expression of RAC-beta serine/threonine-protein kinase (AKT2).	[12]
Vitamin C	DMXJ7O8	Approved	Vitamin C affects the expression of RAC-beta serine/threonine-protein kinase (AKT2).	[17]
Hydrocortisone	DMGEMB7	Approved	Hydrocortisone decreases the expression of RAC-beta serine/threonine-protein kinase (AKT2).	[18]
Methimazole	DM25FL8	Approved	Methimazole decreases the expression of RAC-beta serine/threonine-protein kinase (AKT2).	[19]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of RAC-beta serine/threonine-protein kinase (AKT2).	[6]
Curcumin	DMQPH29	Phase 3	Curcumin decreases the expression of RAC-beta serine/threonine-protein kinase (AKT2).	[20]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of RAC-beta serine/threonine-protein kinase (AKT2).	[22]
GSK2141795	DMSHE70	Phase 2	GSK2141795 decreases the activity of RAC-beta serine/threonine-protein kinase (AKT2).	[24]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of RAC-beta serine/threonine-protein kinase (AKT2).	[28]
Microcystin-LR	DMTMLRN	Investigative	Microcystin-LR increases the expression of RAC-beta serine/threonine-protein kinase (AKT2).	[31]
Maleic Acid	DM4L0R7	Investigative	Maleic Acid decreases the expression of RAC-beta serine/threonine-protein kinase (AKT2).	[32]
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⏷ Show the Full List of 24 Drug(s)

7 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Paclitaxel	DMLB81S	Approved	Paclitaxel increases the phosphorylation of RAC-beta serine/threonine-protein kinase (AKT2).	[13]
Rigosertib	DMOSTXF	Phase 3	Rigosertib decreases the phosphorylation of RAC-beta serine/threonine-protein kinase (AKT2).	[21]
Triciribine	DM8IC5H	Phase 1/2	Triciribine decreases the phosphorylation of RAC-beta serine/threonine-protein kinase (AKT2).	[25]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of RAC-beta serine/threonine-protein kinase (AKT2).	[26]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of RAC-beta serine/threonine-protein kinase (AKT2).	[27]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of RAC-beta serine/threonine-protein kinase (AKT2).	[29]
Chlorpyrifos	DMKPUI6	Investigative	Chlorpyrifos decreases the phosphorylation of RAC-beta serine/threonine-protein kinase (AKT2).	[30]
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⏷ Show the Full List of 7 Drug(s)

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
DNCB	DMDTVYC	Phase 2	DNCB affects the binding of RAC-beta serine/threonine-protein kinase (AKT2).	[23]
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References

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