P31751 (AKT2_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
RAC-beta serine/threonine-protein kinase
EC=2.7.11.1

Alternative name(s):
Protein kinase Akt-2
Protein kinase B beta
Short name=PKB beta
RAC-PK-beta

Gene names

Name:

AKT2

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	481 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

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 PI3P-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 (PI3K) 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. Ref.10 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. 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'. Ref.10
Catalytic activity	ATP + a protein = ADP + a phosphoprotein.
Enzyme regulation	Two specific sites, one in the kinase domain (Thr-309) and the other in the C-terminal regulatory region (Ser-474), need to be phosphorylated for its full activation. Aminofurazans are potent AKT2 inhibitors. Ref.24 Ref.25
Subunit structure	Interacts (via PH domain) with MTCP1, TCL1A AND TCL1B. Interacts with CLK2, PBH2 and TRAF6. Ref.7 Ref.10 Ref.14
Subcellular location	Cytoplasm. Nucleus. Cell membrane; Peripheral membrane protein. Note: Localizes within both nucleus and cytoplasm of proliferative primary myoblasts and mostly within the nucleus of differentiated primary myoblasts. By virtue of the N-terminal PH domain, is recruited to sites of the plasma membrane containing increased PI(3,4,5)P3 or PI(3,4)P2. Ref.10
Tissue specificity	Expressed in all cell types so far analyzed.
Domain	Binding of the PH domain to phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P3) following phosphatidylinositol 3-kinase alpha (PIK3CA) activity results in its targeting to the plasma membrane.
Post-translational modification	Phosphorylation on Thr-309 and Ser-474 is required for full activity. Ubiquitinated; undergoes both 'Lys-48'- and 'Lys-63'-linked polyubiquitination. TRAF6-induced 'Lys-63'-linked AKT2 ubiquitination. When fully phosphorylated and translocated into the nucleus, undergoes 'Lys-48'-polyubiquitination catalyzed by TTC3, leading to its degradation by the proteasome. Ref.6 Ref.8 Ref.12 Ref.20 O-GlcNAcylation at Thr-306 and Thr-313 inhibits activating phosphorylation at Thr-309 via disrupting the interaction between AKT and PDK1 By similarity.
Involvement in disease	Defects in AKT2 are a cause of susceptibility to breast cancer (BC). AKT2 promotes metastasis of tumor cells without affecting the latency of tumor development. With AKT3, plays also a pivotal role in the biology of glioblastoma. Diabetes mellitus, non-insulin-dependent (NIDDM) [MIM:125853]: A multifactorial disorder of glucose homeostasis caused by a lack of sensitivity to the body's own insulin. Affected individuals usually have an obese body habitus and manifestations of a metabolic syndrome characterized by diabetes, insulin resistance, hypertension and hypertriglyceridemia. The disease results in long-term complications that affect the eyes, kidneys, nerves, and blood vessels. Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.26 Ref.28 Hypoinsulinemic hypoglycemia with hemihypertrophy (HIHGHH) [MIM:240900]: A disorder characterized by hypoglycemia, low insulin levels, low serum levels of ketone bodies and branched-chain amino acids, left-sided hemihypertrophy, neonatal macrosomia, reduced consciousness and hypoglycemic seizures. Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.29
Sequence similarities	Belongs to the protein kinase superfamily. AGC Ser/Thr protein kinase family. RAC subfamily. Contains 1 AGC-kinase C-terminal domain. Contains 1 PH domain. Contains 1 protein kinase domain.
Caution	In light of strong homologies in the primary amino acid sequence, the 3 AKT kinases were long surmised to play redundant and overlapping roles. More recent studies has brought into question the redundancy within AKT kinase isoforms and instead pointed to isoform specific functions in different cellular events and diseases. AKT1 is more specifically involved in cellular survival pathways, by inhibiting apoptotic processes; whereas AKT2 is more specific for the insulin receptor signaling pathway. Moreover, while AKT1 and AKT2 are often implicated in many aspects of cellular transformation, the 2 isoforms act in a complementary opposing manner. The role of AKT3 is less clear, though it appears to be predominantly expressed in brain.
Biophysicochemical properties	Kinetic parameters: KM=358.4 µM for ATP (for purified and in vitro activated AKT2) Ref.9 KM=3.4 µM for peptide substrate (for purified and in vitro activated AKT2) KM=564 µM for ATP (for recombinant myristoylated AKT2 expressed and immunoprecipitated from Rat-1 cells) KM=2.3 µM for peptide substrate (for recombinant myristoylated AKT2 expressed and immunoprecipitated from Rat-1 cells)

Ontologies

Keywords
Biological process	Apoptosis Carbohydrate metabolism Glucose metabolism Glycogen biosynthesis Glycogen metabolism Sugar transport Translation regulation Transport
Cellular component	Cell membrane Cytoplasm Membrane Nucleus
Coding sequence diversity	Polymorphism
Disease	Diabetes mellitus Disease mutation Proto-oncogene
Ligand	ATP-binding Nucleotide-binding
Molecular function	Developmental protein Kinase Serine/threonine-protein kinase Transferase
PTM	Disulfide bond Glycoprotein Phosphoprotein Ubl conjugation
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	activation of Ral GTPase activity Inferred from electronic annotation. Source: Compara apoptotic process Inferred from electronic annotation. Source: UniProtKB-KW carbohydrate transport Inferred from electronic annotation. Source: UniProtKB-KW fat cell differentiation Traceable author statement Ref.18. Source: UniProtKB glucose metabolic process Inferred from electronic annotation. Source: UniProtKB-KW glycogen biosynthetic process Inferred from electronic annotation. Source: UniProtKB-KW insulin receptor signaling pathway Traceable author statement Ref.18. Source: UniProtKB intracellular protein transmembrane transport Inferred from sequence or structural similarity. Source: UniProtKB mammary gland epithelial cell differentiation Traceable author statement Ref.18. Source: UniProtKB negative regulation of plasma membrane long-chain fatty acid transport Inferred from mutant phenotype PubMed 16814735. Source: BHF-UCL peripheral nervous system myelin maintenance Inferred from electronic annotation. Source: Compara positive regulation of cell motility Inferred from mutant phenotype PubMed 17332325. Source: BHF-UCL positive regulation of fatty acid beta-oxidation Inferred from mutant phenotype PubMed 16814735. Source: BHF-UCL positive regulation of glucose import Inferred from mutant phenotype PubMed 16814735. Source: BHF-UCL positive regulation of glucose import in response to insulin stimulus Inferred from electronic annotation. Source: Compara positive regulation of glycogen biosynthetic process Inferred from mutant phenotype PubMed 16814735. Source: BHF-UCL positive regulation of protein phosphorylation Inferred from sequence or structural similarity. Source: UniProtKB positive regulation of protein targeting to membrane Inferred from sequence or structural similarity. Source: UniProtKB positive regulation of vesicle fusion Inferred from sequence or structural similarity. Source: UniProtKB protein localization to plasma membrane Inferred from electronic annotation. Source: Compara regulation of JNK cascade Inferred from electronic annotation. Source: Compara regulation of cell cycle arrest Traceable author statement Ref.18. Source: UniProtKB regulation of cell migration Traceable author statement Ref.18. Source: UniProtKB regulation of translation Inferred from electronic annotation. Source: UniProtKB-KW
Cellular_component	cell cortex Inferred from sequence or structural similarity. Source: UniProtKB cytosol Traceable author statement. Source: Reactome lamellipodium Inferred from electronic annotation. Source: Compara nucleus Inferred from direct assay Ref.12. Source: UniProtKB ruffle membrane Inferred from sequence or structural similarity. Source: UniProtKB
Molecular_function	ATP binding Inferred from direct assay Ref.9. Source: UniProtKB phospholipid binding Inferred from electronic annotation. Source: InterPro protein serine/threonine kinase activity Inferred from direct assay Ref.9. Source: UniProtKB
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
GSK3B	P49841	2	EBI-296058,EBI-373586
HSP90AB1	P08238	2	EBI-296058,EBI-352572
VIM	P08670	6	EBI-296058,EBI-353844

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 481

481

RAC-beta serine/threonine-protein kinase

PRO_0000085608

Regions

Domain

5 – 108

104

PH

Domain

152 – 409

258

Protein kinase

Domain

410 – 481

72

AGC-kinase C-terminal

Nucleotide binding

158 – 166

9

ATP By similarity

Region

230 – 232

3

Inhibitor binding

Region

277 – 279

3

Inhibitor binding

Region

292 – 293

2

Inhibitor binding

Sites

Active site

275

1

Proton acceptor By similarity

Binding site

181

1

ATP By similarity

Binding site

181

1

Inhibitor

Binding site

200

1

Inhibitor

Binding site

232

1

Inhibitor; via amide nitrogen

Binding site

236

1

Inhibitor

Binding site

279

1

Inhibitor; via carbonyl oxygen

Binding site

280

1

Manganese

Binding site

293

1

Inhibitor

Binding site

293

1

Manganese

Binding site

294

1

Inhibitor; via amide nitrogen

Amino acid modifications

Modified residue

126

1

Phosphoserine Ref.11

Modified residue

309

1

Phosphothreonine; by PDPK1 Ref.6 Ref.8 Ref.12 Ref.20

Modified residue

447

1

Phosphoserine Ref.13

Modified residue

451

1

Phosphothreonine Ref.13

Modified residue

474

1

Phosphoserine Ref.8 Ref.12 Ref.13

Modified residue

478

1

Phosphoserine Ref.13

Glycosylation

128

1

O-linked (GlcNAc...) By similarity

Glycosylation

131

1

O-linked (GlcNAc...) By similarity

Glycosylation

306

1

O-linked (GlcNAc...) By similarity

Glycosylation

313

1

O-linked (GlcNAc...) By similarity

Disulfide bond

60 ↔ 77

By similarity

Disulfide bond

297 ↔ 311

Ref.21

Natural variations

Natural variant

17

1

E → K in HIHGHH; exhibits plasma membrane localization in serum-starved cells and produced inappropriate tonic nuclear exclusion of FOXO1 in preadipocytes. Ref.29

VAR_067309

Natural variant

188

1

I → V. Ref.27
Corresponds to variant rs55859611 [ dbSNP | Ensembl ].

VAR_040356

Natural variant

208

1

R → K. Ref.27
Corresponds to variant rs35817154 [ dbSNP | Ensembl ].

VAR_040357

Natural variant

274

1

R → H in NIDDM; associated with typical metabolic dyslipidemia with elevated fastin triglyceride, high VLDL triglyceride/cholesterol ratios, low HDL cholesterol levels and high small dense LDL levels; de novo lipogenesis and liver fat are also significantly elevated in this subject. Ref.26 Ref.28

VAR_067310

Experimental info

Mutagenesis

309

1

T → A: Impairs interaction with TTC3; when associated with A-474. Ref.8 Ref.12

Mutagenesis

309

1

T → E: Constitutively active; when associated with D-474. Ref.8 Ref.12

Mutagenesis

474

1

S → A: Impairs interaction with TTC3; when associated with A-309. Ref.8 Ref.12

Mutagenesis

474

1

S → D: Constitutively active; when associated with E-309. Ref.8 Ref.12

Sequence conflict

478 – 481

4

SIRE → FREEKDLLMSLFVSLILFSD FSSLKSHSFSSNFILLSFSS LKK in AAA36585. Ref.1

Secondary structure

1

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481

Helix Strand Turn

Details...

Beta strand

6 – 15

10

Beta strand

17 – 20

4

Beta strand

22 – 30

9

Turn

31 – 33

3

Beta strand

34 – 40

7

Beta strand

45 – 47

3

Beta strand

52 – 56

5

Beta strand

58 – 60

3

Beta strand

62 – 65

4

Beta strand

67 – 75

9

Beta strand

86 – 92

7

Helix

93 – 110

18

Helix

149 – 151

3

Beta strand

152 – 160

9

Beta strand

162 – 171

10

Turn

172 – 174

3

Beta strand

177 – 184

8

Helix

185 – 190

6

Helix

194 – 205

12

Beta strand

215 – 220

6

Beta strand

222 – 230

9

Helix

237 – 244

8

Helix

249 – 268

20

Beta strand

280 – 283

4

Beta strand

289 – 291

3

Beta strand

298 – 300

3

Beta strand

310 – 312

3

Helix

314 – 316

3

Helix

319 – 322

4

Beta strand

323 – 325

3

Helix

331 – 345

15

Beta strand

351 – 353

3

Helix

355 – 364

10

Beta strand

371 – 373

3

Helix

375 – 384

10

Turn

389 – 391

3

Turn

393 – 395

3

Turn

397 – 399

3

Helix

400 – 404

5

Helix

407 – 409

3

Helix

414 – 418

5

Beta strand

431 – 434

4

Beta strand

437 – 439

3

Helix

441 – 444

4

Beta strand

474 – 476

3

Turn

477 – 479

3

Sequences

	Sequence		Length	Mass (Da)
	P31751 [UniParc]. Last modified November 1, 1995. Version 2. Checksum: B18C87A7246BFB24	FASTA	481	55,769
	10 20 30 40 50 60 MNEVSVIKEG WLHKRGEYIK TWRPRYFLLK SDGSFIGYKE RPEAPDQTLP PLNNFSVAEC 70 80 90 100 110 120 QLMKTERPRP NTFVIRCLQW TTVIERTFHV DSPDEREEWM RAIQMVANSL KQRAPGEDPM 130 140 150 160 170 180 DYKCGSPSDS STTEEMEVAV SKARAKVTMN DFDYLKLLGK GTFGKVILVR EKATGRYYAM 190 200 210 220 230 240 KILRKEVIIA KDEVAHTVTE SRVLQNTRHP FLTALKYAFQ THDRLCFVME YANGGELFFH 250 260 270 280 290 300 LSRERVFTEE RARFYGAEIV SALEYLHSRD VVYRDIKLEN LMLDKDGHIK ITDFGLCKEG 310 320 330 340 350 360 ISDGATMKTF CGTPEYLAPE VLEDNDYGRA VDWWGLGVVM YEMMCGRLPF YNQDHERLFE 370 380 390 400 410 420 LILMEEIRFP RTLSPEAKSL LAGLLKKDPK QRLGGGPSDA KEVMEHRFFL SINWQDVVQK 430 440 450 460 470 480 KLLPPFKPQV TSEVDTRYFD DEFTAQSITI TPPDRYDSLG LLELDQRTHF PQFSYSASIR E

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Molecular cloning of a second form of rac protein kinase." Jones P.F., Jakubowicz T., Hemmings B.A. Cell Regul. 2:1001-1009(1991) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Epithelium.
[2]	"AKT2, a putative oncogene encoding a member of a subfamily of protein-serine/threonine kinases, is amplified in human ovarian carcinomas." Cheng J.Q., Godwin A.K., Bellacosa A., Taguchi T., Franke T.F., Hamilton T.C., Tsichlis P.N., Testa J.R. Proc. Natl. Acad. Sci. U.S.A. 89:9267-9271(1992) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[3]	"Complete sequencing and characterization of 21,243 full-length human cDNAs." Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S. , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S. Nat. Genet. 36:40-45(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Placenta.
[4]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
[5]	NIEHS SNPs program Submitted (AUG-2004) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 237-277.
[6]	"Activation of protein kinase B beta and gamma isoforms by insulin in vivo and by 3-phosphoinositide-dependent protein kinase-1 in vitro: comparison with protein kinase B alpha." Walker K.S., Deak M., Paterson A., Hudson K., Cohen P., Alessi D.R. Biochem. J. 331:299-308(1998) [PubMed] [Europe PMC] [Abstract] Cited for: CHARACTERIZATION, PHOSPHORYLATION AT THR-309 BY PDPK1.
[7]	"The protooncogene TCL1 is an Akt kinase coactivator." Laine J., Kuenstle G., Obata T., Sha M., Noguchi M. Mol. Cell 6:395-407(2000) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH MTCP1; TCL1A AND TCL1B.
[8]	"Activation of a GST-tagged AKT2/PKBbeta." Baer K., Lisinski I., Gompert M., Stuhlmann D., Schmolz K., Klein H.W., Al-Hasani H. Biochim. Biophys. Acta 1725:340-347(2005) [PubMed] [Europe PMC] [Abstract] Cited for: MUTAGENESIS OF THR-309 AND SER-474, PHOSPHORYLATION AT THR-309 AND SER-474.
[9]	"Kinetic mechanism of AKT/PKB enzyme family." Zhang X., Zhang S., Yamane H., Wahl R., Ali A., Lofgren J.A., Kendall R.L. J. Biol. Chem. 281:13949-13956(2006) [PubMed] [Europe PMC] [Abstract] Cited for: BIOPHYSICOCHEMICAL PROPERTIES.
[10]	"Akt2 is implicated in skeletal muscle differentiation and specifically binds Prohibitin2/REA." Heron-Milhavet L., Mamaeva D., Rochat A., Lamb N.J., Fernandez A. J. Cell. Physiol. 214:158-165(2008) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH PBH2.
[11]	"A quantitative atlas of mitotic phosphorylation." Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., Elledge S.J., Gygi S.P. Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-126, MASS SPECTROMETRY. Tissue: Cervix carcinoma.
[12]	"The E3 ligase TTC3 facilitates ubiquitination and degradation of phosphorylated Akt." Suizu F., Hiramuki Y., Okumura F., Matsuda M., Okumura A.J., Hirata N., Narita M., Kohno T., Yokota J., Bohgaki M., Obuse C., Hatakeyama S., Obata T., Noguchi M. Dev. Cell 17:800-810(2009) [PubMed] [Europe PMC] [Abstract] Cited for: UBIQUITINATION BY TTC3, PHOSPHORYLATION AT THR-309 AND SER-474, MUTAGENESIS OF THR-309 AND SER-474.
[13]	"Quantitative phosphoproteomic analysis of T cell receptor signaling reveals system-wide modulation of protein-protein interactions." Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K., Rodionov V., Han D.K. Sci. Signal. 2:RA46-RA46(2009) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-447; THR-451; SER-474 AND SER-478, MASS SPECTROMETRY. Tissue: Leukemic T-cell.
[14]	"The E3 ligase TRAF6 regulates Akt ubiquitination and activation." Yang W.-L., Wang J., Chan C.-H., Lee S.-W., Campos A.D., Lamothe B., Hur L., Grabiner B.C., Lin X., Darnay B.G., Lin H.-K. Science 325:1134-1138(2009) [PubMed] [Europe PMC] [Abstract] Cited for: UBIQUITINATION, INTERACTION WITH TRAF6.
[15]	"Akt2 and Akt3 play a pivotal role in malignant gliomas." Mure H., Matsuzaki K., Kitazato K.T., Mizobuchi Y., Kuwayama K., Kageji T., Nagahiro S. Neuro-oncol. 12:221-232(2010) [PubMed] [Europe PMC] [Abstract] Cited for: INVOLVEMENT IN CANCER.
[16]	"Initial characterization of the human central proteome." Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J. BMC Syst. Biol. 5:17-17(2011) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[17]	"Akt signalling in health and disease." Hers I., Vincent E.E., Tavare J.M. Cell. Signal. 23:1515-1527(2011) [PubMed] [Europe PMC] [Abstract] Cited for: REVIEW ON FUNCTION.
[18]	"Akt1 and Akt2: differentiating the aktion." Heron-Milhavet L., Khouya N., Fernandez A., Lamb N.J. Histol. Histopathol. 26:651-662(2011) [PubMed] [Europe PMC] [Abstract] Cited for: REVIEW ON FUNCTION.
[19]	"Molecular mechanism for the regulation of protein kinase B/Akt by hydrophobic motif phosphorylation." Yang J., Cron P., Thompson V., Good V.M., Hess D., Hemmings B.A., Barford D. Mol. Cell 9:1227-1240(2002) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF 146-480.
[20]	"Crystal structure of an activated Akt/protein kinase B ternary complex with GSK3-peptide and AMP-PNP." Yang J., Cron P., Good V.M., Thompson V., Hemmings B.A., Barford D. Nat. Struct. Biol. 9:940-944(2002) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.60 ANGSTROMS) OF 146-467 IN COMPLEX WITH PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER AND MANGANESE, PHOSPHORYLATION AT THR-309.
[21]	"Crystal structure of an inactive Akt2 kinase domain." Huang X., Begley M., Morgenstern K.A., Gu Y., Rose P., Zhao H., Zhu X. Structure 11:21-30(2003) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) OF 143-481, ATP-BINDING, SUBSTRATE-BINDING, DISULFIDE BOND.
[22]	"Solution structure and backbone dynamics of the pleckstrin homology domain of the human protein kinase B (PKB/Akt). Interaction with inositol phosphates." Auguin D., Barthe P., Auge-Senegas M.T., Stern M.H., Noguchi M., Roumestand C. J. Biomol. NMR 28:137-155(2004) [PubMed] [Europe PMC] [Abstract] Cited for: STRUCTURE BY NMR OF 1-111.
[23]	"A structural comparison of inhibitor binding to PKB, PKA and PKA-PKB chimera." Davies T.G., Verdonk M.L., Graham B., Saalau-Bethell S., Hamlett C.C., McHardy T., Collins I., Garrett M.D., Workman P., Woodhead S.J., Jhoti H., Barford D. J. Mol. Biol. 367:882-894(2007) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.8 ANGSTROMS) OF 146-467, INHIBITOR-BINDING.
[24]	"Identification of 4-(2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-7-{[(3S)-3-piperidinylmethyl]oxy}-1H-imidazo[4,5-c]pyridin-4-yl)-2-methyl-3-butyn-2-ol (GSK690693), a novel inhibitor of AKT kinase." Heerding D.A., Rhodes N., Leber J.D., Clark T.J., Keenan R.M., Lafrance L.V., Li M., Safonov I.G., Takata D.T., Venslavsky J.W., Yamashita D.S., Choudhry A.E., Copeland R.A., Lai Z., Schaber M.D., Tummino P.J., Strum S.L., Wood E.R. , Duckett D.R., Eberwein D., Knick V.B., Lansing T.J., McConnell R.T., Zhang S., Minthorn E.A., Concha N.O., Warren G.L., Kumar R. J. Med. Chem. 51:5663-5679(2008) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 146-480, ENZYME REGULATION.
[25]	"Aminofurazans as potent inhibitors of AKT kinase." Rouse M.B., Seefeld M.A., Leber J.D., McNulty K.C., Sun L., Miller W.H., Zhang S., Minthorn E.A., Concha N.O., Choudhry A.E., Schaber M.D., Heerding D.A. Bioorg. Med. Chem. Lett. 19:1508-1511(2009) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF 146-480, ENZYME REGULATION.
[26]	"A family with severe insulin resistance and diabetes due to a mutation in AKT2." George S., Rochford J.J., Wolfrum C., Gray S.L., Schinner S., Wilson J.C., Soos M.A., Murgatroyd P.R., Williams R.M., Acerini C.L., Dunger D.B., Barford D., Umpleby A.M., Wareham N.J., Davies H.A., Schafer A.J., Stoffel M., O'Rahilly S., Barroso I. Science 304:1325-1328(2004) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT NIDDM HIS-274.
[27]	"Patterns of somatic mutation in human cancer genomes." Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G. , Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R. Nature 446:153-158(2007) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS [LARGE SCALE ANALYSIS] VAL-188 AND LYS-208.
[28]	"Postreceptor insulin resistance contributes to human dyslipidemia and hepatic steatosis." Semple R.K., Sleigh A., Murgatroyd P.R., Adams C.A., Bluck L., Jackson S., Vottero A., Kanabar D., Charlton-Menys V., Durrington P., Soos M.A., Carpenter T.A., Lomas D.J., Cochran E.K., Gorden P., O'Rahilly S., Savage D.B. J. Clin. Invest. 119:315-322(2009) [PubMed] [Europe PMC] [Abstract] Cited for: ASSOCIATION OF VARIANT NIDDM HIS-274 WITH TYPICAL METABOLIC DYSLIPIDEMIA.
[29]	"An activating mutation of AKT2 and human hypoglycemia." Hussain K., Challis B., Rocha N., Payne F., Minic M., Thompson A., Daly A., Scott C., Harris J., Smillie B.J., Savage D.B., Ramaswami U., De Lonlay P., O'Rahilly S., Barroso I., Semple R.K. Science 334:474-474(2011) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT HIHGHH LYS-17.
+	Additional computationally mapped references.

Web resources

Atlas of Genetics and Cytogenetics in Oncology and Haematology

NIEHS-SNPs

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

M77198 mRNA. Translation: AAA36585.1.
M95936 mRNA. Translation: AAA58364.1.
AK314619 mRNA. Translation: BAG37185.1.
BC120994 mRNA. Translation: AAI20995.1.
AY708392 Genomic DNA. Translation: AAT97984.1.

IPI

IPI00012870.

PIR

A46288.

RefSeq

NP_001617.1. NM_001626.4.

UniGene

Hs.631535.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1GZK	X-ray	2.30	A	146-460	[»]
1GZN	X-ray	2.50	A	146-480	[»]
1GZO	X-ray	2.75	A	146-460	[»]
1MRV	X-ray	2.80	A	143-481	[»]
1MRY	X-ray	2.80	A	143-481	[»]
1O6K	X-ray	1.70	A	146-481	[»]
1O6L	X-ray	1.60	A	146-467	[»]
1P6S	NMR	-	A	1-111	[»]
2JDO	X-ray	1.80	A	146-467	[»]
2JDR	X-ray	2.30	A	146-467	[»]
2UW9	X-ray	2.10	A	146-467	[»]
2X39	X-ray	1.93	A	146-467	[»]
2XH5	X-ray	2.72	A	146-467	[»]
3D0E	X-ray	2.00	A/B	146-480	[»]
3E87	X-ray	2.30	A/B	146-480	[»]
3E88	X-ray	2.50	A/B	146-480	[»]
3E8D	X-ray	2.70	A/B	146-480	[»]

DisProt

DP00304.

ProteinModelPortal

P31751.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-32583N.

IntAct

P31751. 19 interactions.

MINT

MINT-87790.

STRING

9606.ENSP00000375892.

PTM databases

PhosphoSite

P31751.

Polymorphism databases

DMDM

1170703.

Proteomic databases

PaxDb

P31751.

PRIDE

P31751.

Protocols and materials databases

DNASU

208.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000392038; ENSP00000375892; ENSG00000105221.
ENST00000424901; ENSP00000399532; ENSG00000105221.

GeneID

208.

KEGG

hsa:208.

UCSC

uc002one.3. human.

Organism-specific databases

CTD

208.

GeneCards

GC19M040736.

HGNC

HGNC:392. AKT2.

HPA

CAB004204.

MIM

125853. phenotype.
164731. gene.
240900. phenotype.

neXtProt

NX_P31751.

Orphanet

79085. Familial partial lipodystrophy due to AKT2 mutations.
293964. Hypoinsulinemic hypoglycemia and body hemihypertrophy.

PharmGKB

PA24685.

GenAtlas

Search...

Phylogenomic databases

eggNOG

COG0515.

HOGENOM

HOG000233033.

HOVERGEN

HBG108317.

InParanoid

P31751.

KO

K04456.

OMA

QWTSVIE.

OrthoDB

EOG40GCQP.

PhylomeDB

P31751.

Enzyme and pathway databases

BRENDA

2.7.11.1. 2681.

Pathway_Interaction_DB

pi3kciaktpathway. Class I PI3K signaling events mediated by Akt.
insulin_pathway. Insulin Pathway.
insulin_glucose_pathway. Insulin-mediated glucose transport.

Reactome

REACT_111045. Developmental Biology.
REACT_111102. Signal Transduction.
REACT_11123. Membrane Trafficking.
REACT_1123. Inhibition of HSL.
REACT_116125. Disease.
REACT_604. Hemostasis.
REACT_6900. Immune System.

Gene expression databases

ArrayExpress

P31751.

Bgee

P31751.

CleanEx

HS_AKT2.

Genevestigator

P31751.

GermOnline

ENSG00000105221. Homo sapiens.

Family and domain databases

Gene3D

2.30.29.30. 1 hit.

InterPro

IPR000961. AGC-kinase_C.
IPR011009. Kinase-like_dom.
IPR011993. PH_like_dom.
IPR017892. Pkinase_C.
IPR001849. Pleckstrin_homology.
IPR000719. Prot_kinase_cat_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR002290. Ser/Thr_dual-sp_kinase_dom.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]

Pfam

PF00169. PH. 1 hit.
PF00069. Pkinase. 1 hit.
PF00433. Pkinase_C. 1 hit.
[Graphical view]

SMART

SM00233. PH. 1 hit.
SM00133. S_TK_X. 1 hit.
SM00220. S_TKc. 1 hit.
[Graphical view]

SUPFAM

SSF56112. Kinase_like. 1 hit.

PROSITE

PS51285. AGC_KINASE_CTER. 1 hit.
PS50003. PH_DOMAIN. 1 hit.
PS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

BindingDB

P31751.

ChEMBL

CHEMBL2431.

ChiTaRS

AKT2. human.

EvolutionaryTrace

P31751.

GenomeRNAi

208.

NextBio

836.

SOURCE

Search...

Entry information

Entry name

AKT2_HUMAN

Accession

Primary (citable) accession number: P31751
Secondary accession number(s): B2RBD8, Q0VAN1, Q68GC0

Entry history

Integrated into UniProtKB/Swiss-Prot:	July 1, 1993
Last sequence update:	November 1, 1995
Last modified:	May 1, 2013
This is version 145 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.