AKT2 (AKT serine/threonine kinase 2)

Gene

• Entrez ID: 208
• Gene name: AKT serine/threonine kinase 2
• Gene symbol: AKT2
• Synonyms: HIHGHH, PKBB, PKBBETA, PRKBB, RAC-BETA
• Chromosome: 19
• Chromosome location: 19q13.2
• Summary: This gene is a putative oncogene encoding a protein belonging to a subfamily of serine/threonine kinases containing SH2-like (Src homology 2-like) domains, which is involved in signaling pathways. The gene serves as an oncogene in the tumorigenesis of cancer cells For example, its overexpression contributes to the malignant phenotype of a subset of human ductal pancreatic cancers. The encoded protein is a general protein kinase capable of phophorylating several known proteins, and has also been implicated in insulin signaling. [provided by RefSeq, Nov 2019]

SNPs

SNP ID	Visualize variation	Clinical significance	Consequence
rs121434593	C>T	Pathogenic	Coding sequence variant, missense variant
rs387906659	C>A,T	Pathogenic	Stop gained, coding sequence variant, missense variant, 5 prime UTR variant
rs778561687	C>A,T	Likely-pathogenic	Missense variant, coding sequence variant
rs1057519754	T>C	Likely-pathogenic	Coding sequence variant, intron variant, missense variant

miRNA

miRTarBase ID	miRNA	Experiments	Reference
MIRT000425	hsa-miR-184	qRT-PCR, Luciferase reporter assay, Western blot	20409325
MIRT000425	hsa-miR-184	PAR-CLIP	20371350
MIRT000425	hsa-miR-184	Luciferase reporter assay, qRT-PCR	27418134
MIRT006104	hsa-miR-203a-3p	Northern blot, qRT-PCR, Western blot	21354697
MIRT006473	hsa-miR-708-5p	Luciferase reporter assay, qRT-PCR	22552290
MIRT022768	hsa-miR-124-3p	Microarray	18668037
MIRT022768	hsa-miR-124-3p	Immunoblot, Luciferase reporter assay, qRT-PCR, Western blot	27175587
MIRT031019	hsa-miR-21-5p	Western blot;Other	20048743
MIRT036081	hsa-miR-1296-5p	CLASH	23622248
MIRT036895	hsa-miR-877-3p	CLASH	23622248
MIRT037571	hsa-miR-744-5p	CLASH	23622248
MIRT042572	hsa-miR-423-3p	CLASH	23622248
MIRT045569	hsa-miR-149-5p	CLASH	23622248
MIRT053175	hsa-miR-612	Immunofluorescence, Luciferase reporter assay, Western blot	24704424
MIRT053175	hsa-miR-612	Immunohistochemistry, Luciferase reporter assay, qRT-PCR, Western blot	23478189
MIRT053175	hsa-miR-612	Luciferase reporter assay, qRT-PCR, Western blot	26158514
MIRT054191	hsa-miR-29a-3p	Immunofluorescence, Immunohistochemistry, Luciferase reporter assay, Northern blot, qRT-PCR, Western blot	25428377
MIRT054191	hsa-miR-29a-3p	Flow, Luciferase reporter assay, qRT-PCR, Western blot, Cell proliferation, apoptosis, cell cycle assays	24076586
MIRT054191	hsa-miR-29a-3p	Immunohistochemistry, Luciferase reporter assay, qRT-PCR, Western blot	26512921
MIRT054192	hsa-miR-29b-3p	Immunofluorescence, Immunohistochemistry, Luciferase reporter assay, Northern blot, qRT-PCR, Western blot	25428377
MIRT054192	hsa-miR-29b-3p	Immunofluorescence, Luciferase reporter assay, qRT-PCR, Microarray, Western blot	25263462
MIRT054193	hsa-miR-29c-3p	Immunofluorescence, Immunohistochemistry, Luciferase reporter assay, Northern blot, qRT-PCR, Western blot	25428377
MIRT437424	hsa-miR-137	PAR-CLIP	20371350
MIRT437424	hsa-miR-137	Immunohistochemistry, Luciferase reporter assay, qRT-PCR, Western blot	26102366
MIRT437424	hsa-miR-137	Luciferase reporter assay, qRT-PCR, Western blot	24465609
MIRT437976	hsa-let-7g-5p	Luciferase reporter assay, qRT-PCR, Western blot	25288334
MIRT437977	hsa-let-7b-5p	Luciferase reporter assay, qRT-PCR, Western blot	25288334
MIRT438208	hsa-miR-302b-3p	qRT-PCR, Western blot	24337067
MIRT568545	hsa-miR-1273e	PAR-CLIP	20371350
MIRT568546	hsa-miR-92b-5p	PAR-CLIP	20371350
MIRT568547	hsa-miR-151b	PAR-CLIP	20371350
MIRT568548	hsa-miR-151a-5p	PAR-CLIP	20371350
MIRT568549	hsa-miR-3678-5p	PAR-CLIP	20371350
MIRT568550	hsa-miR-7845-5p	PAR-CLIP	20371350
MIRT568551	hsa-miR-4517	PAR-CLIP	20371350
MIRT568552	hsa-miR-4753-5p	PAR-CLIP	20371350
MIRT568553	hsa-miR-6768-3p	PAR-CLIP	20371350
MIRT568554	hsa-miR-126-3p	PAR-CLIP	20371350
MIRT731613	hsa-miR-2861	Luciferase reporter assay, Western blot	27364926
MIRT733721	hsa-miR-148a-5p	Luciferase reporter assay, qRT-PCR, Western blot	27878305
MIRT734218	hsa-miR-143-3p	Luciferase reporter assay, Microarray, qRT-PCR, Western blot	28404925

Transcription factors

Transcription factor	Regulation	Reference
NFKB1	Repression	20514445
PROX1	Repression	22982861
RELA	Repression	20514445
TWIST1	Activation	21876555;22982861

Gene ontology (GO)

GO ID	Ontology	Definition	Evidence	Reference
GO:0001934	Process	Positive regulation of protein phosphorylation	ISS
GO:0004674	Function	Protein serine/threonine kinase activity	IBA	21873635
GO:0004674	Function	Protein serine/threonine kinase activity	IDA	10983986, 16540465
GO:0004674	Function	Protein serine/threonine kinase activity	TAS	21432781
GO:0005515	Function	Protein binding	IPI	10490823, 10983986, 12434148, 16417406, 16792529, 17030088, 19713527, 20059950, 20856200, 21291857, 21737686, 22939624, 23823123, 32296183
GO:0005524	Function	ATP binding	IDA	16540465
GO:0005634	Component	Nucleus	IDA	20059950
GO:0005634	Component	Nucleus	TAS	21432781
GO:0005654	Component	Nucleoplasm	IDA
GO:0005654	Component	Nucleoplasm	TAS
GO:0005769	Component	Early endosome	IEA
GO:0005829	Component	Cytosol	IDA
GO:0005829	Component	Cytosol	TAS
GO:0005886	Component	Plasma membrane	ISS
GO:0005886	Component	Plasma membrane	TAS	21432781
GO:0005938	Component	Cell cortex	ISS
GO:0005978	Process	Glycogen biosynthetic process	IEA
GO:0006006	Process	Glucose metabolic process	IEA
GO:0006417	Process	Regulation of translation	IEA
GO:0006464	Process	Cellular protein modification process	TAS	1409633
GO:0007165	Process	Signal transduction	TAS	21432781
GO:0008284	Process	Positive regulation of cell population proliferation	IMP	10983986
GO:0008286	Process	Insulin receptor signaling pathway	IMP	16814735
GO:0008286	Process	Insulin receptor signaling pathway	TAS	21432781
GO:0008643	Process	Carbohydrate transport	IEA
GO:0010748	Process	Negative regulation of long-chain fatty acid import across plasma membrane	IMP	16814735
GO:0010907	Process	Positive regulation of glucose metabolic process	IMP	16814735
GO:0010918	Process	Positive regulation of mitochondrial membrane potential	IMP	10983986
GO:0018105	Process	Peptidyl-serine phosphorylation	IBA	21873635
GO:0030334	Process	Regulation of cell migration	TAS	21432781
GO:0030335	Process	Positive regulation of cell migration	IDA	25428377
GO:0031340	Process	Positive regulation of vesicle fusion	ISS
GO:0032000	Process	Positive regulation of fatty acid beta-oxidation	IMP	16814735
GO:0032287	Process	Peripheral nervous system myelin maintenance	IEA
GO:0032587	Component	Ruffle membrane	ISS
GO:0032869	Process	Cellular response to insulin stimulus	IMP	16814735
GO:0032991	Component	Protein-containing complex	IDA	10983986
GO:0035556	Process	Intracellular signal transduction	IBA	21873635
GO:0043066	Process	Negative regulation of apoptotic process	IMP	10983986
GO:0043231	Component	Intracellular membrane-bounded organelle	IDA
GO:0045444	Process	Fat cell differentiation	TAS	21432781
GO:0045725	Process	Positive regulation of glycogen biosynthetic process	IMP	16814735
GO:0046326	Process	Positive regulation of glucose import	IMP	16814735
GO:0046872	Function	Metal ion binding	IEA
GO:0060644	Process	Mammary gland epithelial cell differentiation	TAS	21432781
GO:0065002	Process	Intracellular protein transmembrane transport	ISS
GO:0071156	Process	Regulation of cell cycle arrest	TAS	21432781
GO:0071486	Process	Cellular response to high light intensity	IEA
GO:0072659	Process	Protein localization to plasma membrane	IEA
GO:0090314	Process	Positive regulation of protein targeting to membrane	ISS
GO:0090630	Process	Activation of GTPase activity	IEA
GO:0097473	Process	Retinal rod cell apoptotic process	IEA
GO:0106310	Function	Protein serine kinase activity	IEA
GO:0106311	Function	Protein threonine kinase activity	IEA
GO:2000147	Process	Positive regulation of cell motility	IMP	17332325

Other IDs

• MIM: 164731
• HGNC: 392
• e!Ensembl: ENSG00000105221

Protein

• UniProt ID: P31751
• Protein name: RAC-beta serine/threonine-protein kinase (EC 2.7.11.1) (Protein kinase Akt-2) (Protein kinase B beta) (PKB beta) (RAC-PK-beta)
• Protein 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.; 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'.
• PDB: 1GZK, 1GZN, 1GZO, 1MRV, 1MRY, 1O6K, 1O6L, 1P6S, 2JDO, 2JDR, 2UW9, 2X39, 2XH5, 3D0E, 3E87, 3E88, 3E8D
• Family and domains:

  Pfam

  Accession	ID	Position in sequence	Description	Type
  PF00169	PH	6 → 108	PH domain	Domain
  PF00069	Pkinase	152 → 409	Protein kinase domain	Domain
  PF00433	Pkinase_C	430 → 475	Protein kinase C terminal domain	Family

• Sequence:

  MNEVSVIKEGWLHKRGEYIKTWRPRYFLLKSDGSFIGYKERPEAPDQTLPPLNNFSVAEC
  QLMKTERPRPNTFVIRCLQWTTVIERTFHVDSPDEREEWMRAIQMVANSLKQRAPGEDPM
  DYKCGSPSDSSTTEEMEVAVSKARAKVTMNDFDYLKLLGKGTFGKVILVREKATGRYYAM
  KILRKEVIIAKDEVAHTVTESRVLQNTRHPFLTALKYAFQTHDRLCFVMEYANGGELFFH
  LSRERVFTEERARFYGAEIVSALEYLHSRDVVYRDIKLENLMLDKDGHIKITDFGLCKEG
  ISDGATMKTFCGTPEYLAPEVLEDNDYGRAVDWWGLGVVMYEMMCGRLPFYNQDHERLFE
  LILMEEIRFPRTLSPEAKSLLAGLLKKDPKQRLGGGPSDAKEVMEHRFFLSINWQDVVQK
  KLLPPFKPQVTSEVDTRYFDDEFTAQSITITPPDRYDSLGLLELDQRTHFPQFSYSASIR
  E

• Sequence length: 481