Q01314 (AKT1_BOVIN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

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

Alternative name(s):
Protein kinase B
Short name=PKB
Protein kinase B alpha
Short name=PKB alpha
RAC-PK-alpha

Gene names

Name:	AKT1
Synonyms:	PKB

Organism

Bos taurus (Bovine) [Reference proteome]

Taxonomic identifier

9913 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Laurasiatheria › Cetartiodactyla › Ruminantia › Pecora › Bovidae › Bovinae › Bos

Protein attributes

Sequence length	480 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	AKT1 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. 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. nuclear translocation. Phosphorylates RAF1 at 'Ser-259' and negatively regulates its activity. Phosphorylation of BAD stimulates its pro-apoptotic activity By similarity. Phosphorylates KAT6A at 'Thr-369' and this phosphorylation inhibits the interaction of KAT6A with PML and negatively regulates its acetylation activity towards p53/TP53 By similarity. AKT1-specific substrates have been recently identified, including palladin (PALLD), which phosphorylation modulates cytoskeletal organization and cell motility; prohibitin (PHB), playing an important role in cell metabolism and proliferation; and CDKN1A, for which phosphorylation at 'Thr-145' induces its release from CDK2 and cytoplasmic relocalization. These recent findings indicate that the AKT1 isoform has a more specific role in cell motility and proliferation. Phosphorylates CLK2 thereby controlling cell survival to ionizing radiation. Phosphorylates SRPK2 and enhances its kinase activity towards SRSF2 and ACIN1 and promotes its nuclear translocation By similarity.
Catalytic activity	ATP + a protein = ADP + a phosphoprotein.
Subunit structure	Interacts (via the C-terminus) with CCDC88A (via its C-terminus) and THEM4 (via its C-terminus). Interacts with AKTIP. Interacts (via PH domain) with MTCP1, TCL1A AND TCL1B. Interacts with TRAF6. Interacts with GRB10; the interaction leads to GRB10 phosphorylation thus promoting YWHAE binding. Interacts with RARA; the interaction phosphorylates RARA and represses its transactivation activity. Interacts with MAP3K5 and TNK2. Interacts with BAD, CLK2, PPP2R5B, STK3 and STK4. Interacts (via PH domain) with SIRT1. Interacts with SRPK2 in a phosphorylation-dependent manner. Interacts with RAF1. Interacts with PKN2 (via C-terminal domain); the interaction occurs with the C-terminus cleavage products of PKN2 in apoptotic cells. Interacts with TRIM13; the interaction ubiquitinates AKT1 leading to its proteasomal degradation. Interacts with and phosphorylated by PDPK1 By similarity.
Subcellular location	Cytoplasm By similarity. Nucleus By similarity. Cell membrane By similarity. Note: Nucleus after activation by integrin-linked protein kinase 1 (ILK1). Nuclear translocation is enhanced by interaction with TCL1A By similarity. Phosphorylation on Tyr-176 by TNK2 results in its localization to the cell membrane where it is targeted for further phosphorylations on Thr-308 and Ser-473 leading to its activation and the activated form translocates to the nucleus By similarity.
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. The PH domain mediates interaction with TNK2 and Tyr-176 is also essential for this interaction By similarity. The AGC-kinase C-terminal mediates interaction with THEM4 By similarity.
Post-translational modification	O-GlcNAcylation at Thr-305 and Thr-312 inhibits activating phosphorylation at Thr-308 via disrupting the interaction between AKT1 and PDPK1. O-GlcNAcylation at Ser-473 also probably interferes with phosphorylation at this site By similarity. Phosphorylation on Thr-308, Ser-473 and Tyr-474 is required for full activity. Activated TNK2 phosphorylates it on Tyr-176 resulting in its binding to the anionic plasma membrane phospholipid PA. This phosphorylated form localizes to the cell membrane, where it is targeted by PDPK1 and PDPK2 for further phosphorylations on Thr-308 and Ser-473 leading to its activation. Ser-473 phosphorylation by mTORC2 favors Thr-308 phosphorylation by PDPK1. Ser-473 phosphorylation is enhanced by signaling through activated FLT3 By similarity. Ser-473 is dephosphorylated by PHLPP. Dephosphorylated at Thr-308 and Ser-473 by PP2A phosphatase. The phosphorylated form of PPP2R5B is required for bridging AKT1 with PP2A phosphatase By similarity. Ref.4 Ubiquitinated; undergoes both 'Lys-48'- and 'Lys-63'-linked polyubiquitination. TRAF6-induced 'Lys-63'-linked AKT1 ubiquitination is critical for phosphorylation and activation. When ubiquitinated, it translocates to the plasma membrane, where it becomes phosphorylated. When fully phosphorylated and translocated into the nucleus, undergoes 'Lys-48'-polyubiquitination catalyzed by TTC3, leading to its degradation by the proteasome. Ubiquitinated via 'Lys-48'-linked polyubiquitination by ZNRF1, leading to its degradation by the proteasome. Also ubiquitinated by TRIM13 leading to its proteasomal degradation By similarity. Ref.4 Acetylated on Lys-14 and Lys-20 by the histone acetyltransferases EP300 and KAT2B. Acetylation results in reduced phosphorylation and inhibition of activity. Deacetylated at Lys-14 and Lys-20 by SIRT1. SIRT1-mediated deacetylation relieves the inhibition 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 Neurogenesis 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	Acetylation Disulfide bond Glycoprotein 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 negative regulation of cysteine-type endopeptidase activity involved in apoptotic process Inferred from sequence or structural similarity. Source: UniProtKB negative regulation of release of cytochrome c from mitochondria Inferred from sequence or structural similarity. Source: UniProtKB regulation of cell migration Inferred from sequence or structural similarity. Source: UniProtKB regulation of neuron projection development Inferred from sequence or structural similarity. Source: UniProtKB regulation of translation Inferred from electronic annotation. Source: UniProtKB-KW
Cellular_component	cytoplasm Inferred from electronic annotation. Source: UniProtKB-SubCell nucleus Inferred from sequence or structural similarity. Source: UniProtKB plasma membrane Inferred from sequence or structural similarity. Source: UniProtKB
Molecular_function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW phospholipid binding Inferred from electronic annotation. Source: InterPro protein serine/threonine kinase activity Inferred from sequence or structural similarity. Source: UniProtKB
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
Ppl	Q9R269	2	EBI-368344,EBI-368293	From a different organism.

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 480	480	RAC-alpha serine/threonine-protein kinase		PRO_0000085604
Regions
	Domain	5 – 108	104	PH
	Domain	150 – 408	259	Protein kinase
	Domain	409 – 480	72	AGC-kinase C-terminal
	Nucleotide binding	156 – 164	9	ATP By similarity
	Region	14 – 19	6	Inositol-(1,3,4,5)-tetrakisphosphate binding By similarity
	Region	23 – 25	3	Inositol-(1,3,4,5)-tetrakisphosphate binding By similarity
	Region	228 – 230	3	Inhibitor binding By similarity
Sites
	Active site	274	1	Proton acceptor By similarity
	Binding site	53	1	Inositol-(1,3,4,5)-tetrakisphosphate By similarity
	Binding site	86	1	Inositol-(1,3,4,5)-tetrakisphosphate By similarity
	Binding site	161	1	Inhibitor; via amide nitrogen By similarity
	Binding site	179	1	ATP By similarity
	Binding site	230	1	Inhibitor; via amide nitrogen By similarity
	Binding site	234	1	Inhibitor By similarity
	Binding site	292	1	Inhibitor By similarity
Amino acid modifications
	Modified residue	14	1	N6-acetyllysine By similarity
	Modified residue	20	1	N6-acetyllysine By similarity
	Modified residue	124	1	Phosphoserine By similarity
	Modified residue	129	1	Phosphoserine; alternate By similarity
	Modified residue	176	1	Phosphotyrosine; by TNK2 By similarity
	Modified residue	308	1	Phosphothreonine; by PDPK1 By similarity
	Modified residue	450	1	Phosphothreonine; by MTOR By similarity
	Modified residue	473	1	Phosphoserine; by MTOR Probable
	Modified residue	474	1	Phosphotyrosine By similarity
	Glycosylation	129	1	O-linked (GlcNAc...) By similarity
	Glycosylation	305	1	O-linked (GlcNAc...) By similarity
	Glycosylation	312	1	O-linked (GlcNAc...) By similarity
	Glycosylation	473	1	O-linked (GlcNAc...); alternate By similarity
	Disulfide bond	60 ↔ 77		By similarity
	Disulfide bond	296 ↔ 310		By similarity
Experimental info
	Sequence conflict	149	1	D → E in CAA43371. Ref.1
	Sequence conflict	153	1	L → V in CAA43371. Ref.1
	Sequence conflict	173 – 174	2	GR → AA in CAA43371. Ref.1
	Sequence conflict	209	1	F → S in CAA43371. Ref.1

Sequences

	Sequence		Length	Mass (Da)
	Q01314 [UniParc]. Last modified July 25, 2006. Version 2. Checksum: 152E6613C4E6ED5A	FASTA	480	55,748
	10 20 30 40 50 60 MNDVAIVKEG WLHKRGEYIK TWRPRYFLLK NDGTFIGYKE RPQDLEQRES PLNNFSVAQC 70 80 90 100 110 120 QLMKTERPRP NTFIIRCLQW TTVIERTFHV ETPEEREEWT TAIQTVADGL KRQEEETMDF 130 140 150 160 170 180 RSGSPGENSG AEEMEVSLAK PKHRVTMNDF EYLKLLGKGT FGKVILVKEK ATGRYYAMKI 190 200 210 220 230 240 LKKEVIVAKD EVAHTLTENR VLQNSRHPFL TALKYSFQTH DRLCFVMEYA NGGELFFHLS 250 260 270 280 290 300 RERVFSEDRA RFYGAEIVSA LDYLHSEKEV VYRDLKLENL MLDKDGHIKI TDFGLCKEGI 310 320 330 340 350 360 KDGATMKTFC GTPEYLAPEV LEDNDYGRAV DWWGLGVVMY EMMCGRLPFY NQDHEKLFEL 370 380 390 400 410 420 ILMEEIRFPR TLSPEAKSLL SGLLKKDPKQ RLGGGSEDAK EIMQHRFFAS IVWQDVYEKK 430 440 450 460 470 480 LSPPFKPQVT SETDTRYFDE EFTAQMITIT PPDQDDSMEG VDSERRPHFP QFSYSASATA

References

[1]	"Molecular cloning and characterisation of a novel putative protein-serine kinase related to the cAMP-dependent and protein kinase C families." Coffer P.J., Woodgett J.R. Eur. J. Biochem. 201:475-481(1991) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Brain.
[2]	Erratum Coffer P.J., Woodgett J.R. Eur. J. Biochem. 205:1217-1218(1992) [PubMed] [Europe PMC] [Abstract] Cited for: SEQUENCE REVISION.
[3]	"Complete sequence of the bovine AKT1 gene." Khatib H. Submitted (OCT-2004) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Brain.
[4]	"PHLPP: a phosphatase that directly dephosphorylates Akt, promotes apoptosis, and suppresses tumor growth." Gao T., Furnari F., Newton A.C. Mol. Cell 18:13-24(2005) [PubMed] [Europe PMC] [Abstract] Cited for: DEPHOSPHORYLATION AT SER-473 BY PHLPP.

Cross-references

Sequence databases
EMBL GenBank DDBJ	X61036 mRNA. Translation: CAA43371.1. AY781100 mRNA. Translation: AAW71957.1.
IPI	IPI00696205.
PIR	S62117.
RefSeq	NP_776411.1. NM_173986.2.
UniGene	Bt.4843.
3D structure databases
ProteinModelPortal	Q01314.
SMR	Q01314. Positions 3-121, 144-478.
ModBase	Search...
Protein-protein interaction databases
IntAct	Q01314. 1 interaction.
STRING	9913.ENSBTAP00000051717.
Proteomic databases
PRIDE	Q01314.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
GeneID	280991.
KEGG	bta:280991.
Organism-specific databases
CTD	207.
Phylogenomic databases
eggNOG	COG0515.
HOGENOM	HOG000233033.
HOVERGEN	HBG108317.
KO	K04456.
Enzyme and pathway databases
BRENDA	2.7.11.1. 908.
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
ChEMBL	CHEMBL1250377.
NextBio	20805091.

Entry information

Entry name

AKT1_BOVIN

Accession

Primary (citable) accession number: Q01314
Secondary accession number(s): Q5ER96

Entry history

Integrated into UniProtKB/Swiss-Prot:	November 1, 1995
Last sequence update:	July 25, 2006
Last modified:	May 1, 2013
This is version 125 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program