P47197 (AKT2_RAT) 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

Rattus norvegicus (Rat)

Taxonomic identifier

10116 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Rattus

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 kinases, 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.2 One of the few specific substrates of AKT2 identified so far 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. AKT2 is also specifically involved in skeletal muscle differentiation. Phosphorylates CLK2 on 'Thr-343'. Ref.2
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 By similarity.
Subunit structure	Interacts (via PH domain) with MTCP1, TCL1A AND TCL1B. Interacts with TRAF6 By similarity. Interacts with CLK2. Ref.2
Subcellular location	Cytoplasm By similarity. Nucleus By similarity. Cell membrane; Peripheral membrane protein By similarity. Note: Localizes within both nucleus and cytoplasm of proliferative primary myoblasts and mostly within the nucleus of differentiated primary myoblasts By similarity. 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 By similarity.
Domain	Binding of the PH domain to the phosphatidylinositol 3-kinase alpha (PIK3CA) results in its targeting to the plasma membrane By similarity.
Post-translational modification	Phosphorylation on Thr-309 and Ser-474 is required for full activity By similarity. 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 By similarity.
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.

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
Ligand	ATP-binding Nucleotide-binding
Molecular function	Developmental protein Kinase Serine/threonine-protein kinase Transferase
PTM	Disulfide bond Phosphoprotein Ubl conjugation
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological process	carbohydrate transport Inferred from electronic annotation. Source: UniProtKB-KW glucose metabolic process Inferred from electronic annotation. Source: UniProtKB-KW glycogen biosynthetic process Inferred from electronic annotation. Source: UniProtKB-KW multicellular organismal development Inferred from electronic annotation. Source: UniProtKB-KW negative regulation of RNA splicing Inferred from mutant phenotype. Source: RGD negative regulation of apoptotic process Inferred from mutant phenotype. Source: RGD negative regulation of cysteine-type endopeptidase activity involved in apoptotic process Inferred from mutant phenotype. Source: RGD positive regulation of cell migration Inferred from mutant phenotype. Source: RGD positive regulation of glucose import Inferred from mutant phenotype. Source: RGD positive regulation of nitric oxide biosynthetic process Inferred from mutant phenotype. Source: RGD positive regulation of peptidyl-serine phosphorylation Inferred from mutant phenotype. Source: RGD positive regulation of positive chemotaxis Inferred from direct assay. Source: RGD positive regulation of signal transduction Inferred from mutant phenotype. Source: RGD positive regulation of sodium ion transport Inferred from mutant phenotype. Source: MGI positive regulation of transcription from RNA polymerase II promoter Inferred from mutant phenotype. Source: RGD protein kinase B signaling cascade Inferred from mutant phenotype. Source: RGD regulation of translation Inferred from electronic annotation. Source: UniProtKB-KW response to muscle activity Inferred from expression pattern. Source: RGD response to osmotic stress Inferred from expression pattern. Source: RGD
Cellular component	cytosol Inferred from direct assay. Source: RGD insulin-responsive compartment Inferred from direct assay. Source: RGD microsome Inferred from direct assay. Source: RGD mitochondrion Inferred from direct assay. Source: RGD nucleoplasm Traceable author statement. Source: Reactome plasma membrane Inferred from direct assay. Source: RGD soluble fraction Inferred from direct assay. Source: RGD
Molecular function	ATP binding Inferred from direct assay. Source: RGD protein kinase C binding Inferred from physical interaction. Source: RGD protein serine/threonine kinase activity Inferred from direct assay. Source: RGD
Complete GO annotation...

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_0000085610
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 By similarity
	Region	277 – 279	3	Inhibitor binding By similarity
	Region	292 – 293	2	Inhibitor binding By similarity
Sites
	Active site	275	1	Proton acceptor By similarity
	Binding site	181	1	ATP By similarity
	Binding site	181	1	Inhibitor By similarity
	Binding site	200	1	Inhibitor By similarity
	Binding site	232	1	Inhibitor; via amide nitrogen By similarity
	Binding site	236	1	Inhibitor By similarity
	Binding site	279	1	Inhibitor; via carbonyl oxygen[2X39] By similarity
	Binding site	280	1	Manganese By similarity
	Binding site	293	1	Inhibitor By similarity
	Binding site	293	1	Manganese By similarity
	Binding site	294	1	Inhibitor; via amide nitrogen By similarity
Amino acid modifications
	Modified residue	126	1	Phosphoserine By similarity
	Modified residue	309	1	Phosphothreonine; by PDPK1 By similarity
	Modified residue	447	1	Phosphoserine By similarity
	Modified residue	451	1	Phosphothreonine By similarity
	Modified residue	474	1	Phosphoserine By similarity
	Modified residue	478	1	Phosphoserine By similarity
	Disulfide bond	60 ↔ 77		By similarity

Sequences

	Sequence		Length	Mass (Da)
	P47197 [UniParc]. Last modified February 1, 1996. Version 1. Checksum: 3C4BE65B2F376F85	FASTA	481	55,543
	10 20 30 40 50 60 MNEVSVIKEG WLHKRGEYIK TWRPRYFLLK SDGSFIGYKE RPEAPDQTLP PLNNFSVAEC 70 80 90 100 110 120 QLMKTERPRP NTFVIRCLQW TTVIERTFHV DSPDEREEWI RAIQMVANSL KQRGPGEDAM 130 140 150 160 170 180 DYKCGSPSDS STSEMMEVAV SKARAKVTMN DFDYLKLLGK GTFGKVILVR EKATGRYYAM 190 200 210 220 230 240 KILRKEVIIA KDEVAHTVTE SRVLQNTRHP FLTALKYAFQ THDRLCFVME YANGGDLFFH 250 260 270 280 290 300 LSRERVFTED RARFYGAEIV SALEYLHSTD VVYRDIKLEN LMLDKDGHIK ITDFGLSKEG 310 320 330 340 350 360 ISDGATMKTF CGTPEYLAPE VLEDNDYGRA VDWWGLGVVM YEMMCGRLPF YNQDHERLFE 370 380 390 400 410 420 LILMEEIRFP RTLGPEAKSL LAGLLKKDPK QRLGGGPSDA KEVMEHRFFL SINWQDVVQK 430 440 450 460 470 480 KLLPPFKPQV TSEVDTRYFD DEFTAQSITI TPPDRYDSLG SLELDQRTHF PQFSYSASIR E

References

[1]	"Molecular cloning of rat RAC protein kinase alpha and beta and their association with protein kinase C zeta." Konishi H., Shinomura T., Kuroda S.I., Ono Y., Kikkawa U. Biochem. Biophys. Res. Commun. 205:817-825(1994) [PubMed: 7999118] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Testis.
[2]	"Cdc2-like kinase 2 is an insulin-regulated suppressor of hepatic gluconeogenesis." Rodgers J.T., Haas W., Gygi S.P., Puigserver P. Cell Metab. 11:23-34(2010) [PubMed: 20074525] [Abstract] Cited for: FUNCTION, INTERACTION WITH CLK2.
[3]	"Akt signalling in health and disease." Hers I., Vincent E.E., Tavare J.M. Cell. Signal. 23:1515-1527(2011) [PubMed: 21620960] [Abstract] Cited for: REVIEW ON FUNCTION.
[4]	"Akt1 and Akt2: differentiating the aktion." Heron-Milhavet L., Khouya N., Fernandez A., Lamb N.J. Histol. Histopathol. 26:651-662(2011) [PubMed: 21432781] [Abstract] Cited for: REVIEW ON FUNCTION.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	D30041 mRNA. Translation: BAA06280.1.
IPI	IPI00212846.
PIR	JC2438.
RefSeq	NP_058789.1. NM_017093.1.
UniGene	Rn.87066.
3D structure databases
ProteinModelPortal	P47197.
SMR	P47197. Positions 1-111, 146-479.
ModBase	Search...
Protein-protein interaction databases
STRING	P47197.
PTM databases
PhosphoSite	P47197.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
GeneID	25233.
KEGG	rno:25233.
UCSC	NM_017093. rat.
Organism-specific databases
CTD	208.
RGD	2082. Akt2.
Phylogenomic databases
eggNOG	roNOG14203.
HOVERGEN	HBG108317.
InParanoid	P47197.
OrthoDB	EOG40GCQP.
PhylomeDB	P47197.
Enzyme and pathway databases
BRENDA	2.7.11.1. 5301.
Reactome	REACT_111984. Signal Transduction. REACT_82403. Hemostasis.
Gene expression databases
ArrayExpress	P47197.
Genevestigator	P47197.
GermOnline	ENSRNOG00000018677. Rattus norvegicus.
Family and domain databases
InterPro	IPR000961. AGC-kinase_C. IPR011009. Kinase-like_dom. IPR011993. PH_type. IPR017892. Pkinase_C. IPR001849. Pleckstrin_homology. IPR000719. Prot_kinase_cat_dom. IPR017441. Protein_kinase_ATP_BS. IPR017442. Se/Thr_kinase-like_dom. IPR008271. Ser/Thr_kinase_AS. IPR002290. Ser/Thr_kinase_dom. [Graphical view]
Gene3D	G3DSA:2.30.29.30. PH_type. 1 hit.
KO	K04456.
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
NextBio	605799.

Entry information

Entry name

AKT2_RAT

Accession

Primary (citable) accession number: P47197

Entry history

Integrated into UniProtKB/Swiss-Prot:	February 1, 1996
Last sequence update:	February 1, 1996
Last modified:	January 25, 2012
This is version 95 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program