AKT2_HUMAN - PTM Information in dbPTM

Basic Information of Protein

• UniProt ID: AKT2_HUMAN
• UniProt AC: P31751
• Protein Name: RAC-beta serine/threonine-protein kinase
• Gene Name: AKT2
• Organism: Homo sapiens (Human).
• Sequence Length: 481
• Subcellular Localization: Cytoplasm. Nucleus. Cell membrane; Peripheral membrane protein. Early endosome . Localizes within both nucleus and cytoplasm of proliferative primary myoblasts and mostly within the nucleus of differentiated primary myoblasts. By virtue of the N-term
• Protein Description: 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'..
• Protein Sequence: MNEVSVIKEGWLHKRGEYIKTWRPRYFLLKSDGSFIGYKERPEAPDQTLPPLNNFSVAECQLMKTERPRPNTFVIRCLQWTTVIERTFHVDSPDEREEWMRAIQMVANSLKQRAPGEDPMDYKCGSPSDSSTTEEMEVAVSKARAKVTMNDFDYLKLLGKGTFGKVILVREKATGRYYAMKILRKEVIIAKDEVAHTVTESRVLQNTRHPFLTALKYAFQTHDRLCFVMEYANGGELFFHLSRERVFTEERARFYGAEIVSALEYLHSRDVVYRDIKLENLMLDKDGHIKITDFGLCKEGISDGATMKTFCGTPEYLAPEVLEDNDYGRAVDWWGLGVVMYEMMCGRLPFYNQDHERLFELILMEEIRFPRTLSPEAKSLLAGLLKKDPKQRLGGGPSDAKEVMEHRFFLSINWQDVVQKKLLPPFKPQVTSEVDTRYFDDEFTAQSITITPPDRYDSLGLLELDQRTHFPQFSYSASIRE

Overview of Protein Modification Sites with Functional and Structural Information

Experimental Post-Translational Modification Sites

* ASA = Accessible Surface Area

Locations	Modification	Substrate Peptides & Secondary Structure	ASA (%)	Reference
1	Acetylation	-------MNEVSVIK -------CCCCEEEE	9.71	22223895
14	Acetylation	IKEGWLHKRGEYIKT EECCCCCCCCCCCCC	60.99	-
14	Ubiquitination	IKEGWLHKRGEYIKT EECCCCCCCCCCCCC	60.99	-
20	Ubiquitination	HKRGEYIKTWRPRYF CCCCCCCCCCCCEEE	40.93	-
20	Acetylation	HKRGEYIKTWRPRYF CCCCCCCCCCCCEEE	40.93	-
30	Ubiquitination	RPRYFLLKSDGSFIG CCEEEEECCCCCEEC	48.96	21890473
30	Ubiquitination	RPRYFLLKSDGSFIG CCEEEEECCCCCEEC	48.96	21890473
30	Ubiquitination	RPRYFLLKSDGSFIG CCEEEEECCCCCEEC	48.96	21890473
31	Phosphorylation	PRYFLLKSDGSFIGY CEEEEECCCCCEECC	47.36	23927012
34	Phosphorylation	FLLKSDGSFIGYKER EEECCCCCEECCCCC	20.77	28355574
38	Phosphorylation	SDGSFIGYKERPEAP CCCCEECCCCCCCCC	12.59	23927012
39	Ubiquitination	DGSFIGYKERPEAPD CCCEECCCCCCCCCC	41.87	-
56	Phosphorylation	LPPLNNFSVAECQLM CCCCCCCCHHEEEEC	23.65	25690035
72	Phosphorylation	TERPRPNTFVIRCLQ CCCCCCCEEEEEEEE	23.20	28857561
81	Phosphorylation	VIRCLQWTTVIERTF EEEEEEEEEEEEEEE	9.75	50564519
87	Phosphorylation	WTTVIERTFHVDSPD EEEEEEEEECCCCHH	12.80	26699800
92	Phosphorylation	ERTFHVDSPDEREEW EEEECCCCHHHHHHH	32.91	26699800
111	Ubiquitination	QMVANSLKQRAPGED HHHHHHHHHHCCCCC	37.24	-
122	Phosphorylation	PGEDPMDYKCGSPSD CCCCCCCCCCCCCCC	11.26	21712546
126	Phosphorylation	PMDYKCGSPSDSSTT CCCCCCCCCCCCCCH	30.60	23401153
128	Phosphorylation	DYKCGSPSDSSTTEE CCCCCCCCCCCCHHH	52.39	25159151
128	O-linked_Glycosylation	DYKCGSPSDSSTTEE CCCCCCCCCCCCHHH	52.39	UniProtKB CARBOHYD
130	Phosphorylation	KCGSPSDSSTTEEME CCCCCCCCCCHHHHH	33.64	23403867
131	Phosphorylation	CGSPSDSSTTEEMEV CCCCCCCCCHHHHHH	44.32	23403867
131	O-linked_Glycosylation	CGSPSDSSTTEEMEV CCCCCCCCCHHHHHH	44.32	UniProtKB CARBOHYD
132	Phosphorylation	GSPSDSSTTEEMEVA CCCCCCCCHHHHHHH	42.02	23403867
133	Phosphorylation	SPSDSSTTEEMEVAV CCCCCCCHHHHHHHH	31.71	23403867
141	Phosphorylation	EEMEVAVSKARAKVT HHHHHHHHHHHCEEE	15.74	23403867
142	Ubiquitination	EMEVAVSKARAKVTM HHHHHHHHHHCEEEC	34.98	-
146	Ubiquitination	AVSKARAKVTMNDFD HHHHHHCEEECCHHH	32.46	-
156	Ubiquitination	MNDFDYLKLLGKGTF CCHHHHHHHHCCCCC	35.12	-
160	Ubiquitination	DYLKLLGKGTFGKVI HHHHHHCCCCCCEEE	55.54	-
177	Phosphorylation	REKATGRYYAMKILR EECCCCCCHHHHHHH	9.27	50564527
178	Phosphorylation	EKATGRYYAMKILRK ECCCCCCHHHHHHHC	10.00	50564543
185	Ubiquitination	YAMKILRKEVIIAKD HHHHHHHCCEEEEEC	53.54	-
191	Ubiquitination	RKEVIIAKDEVAHTV HCCEEEEECCCCCCC	43.97	-
201	Phosphorylation	VAHTVTESRVLQNTR CCCCCCHHHHHHHCC	20.51	30631047
242	Phosphorylation	GELFFHLSRERVFTE CEEEEEECHHHCCCH	24.43	46161789
277	Ubiquitination	DVVYRDIKLENLMLD CCEECEECHHHEEEC	54.78	21906983
285	Ubiquitination	LENLMLDKDGHIKIT HHHEEECCCCCEEEC	62.74	-
290	Ubiquitination	LDKDGHIKITDFGLC ECCCCCEEECCCCCC	33.60	-
292	Phosphorylation	KDGHIKITDFGLCKE CCCCEEECCCCCCCC	21.92	-
298	Ubiquitination	ITDFGLCKEGISDGA ECCCCCCCCCCCCCC	65.11	-
302	Phosphorylation	GLCKEGISDGATMKT CCCCCCCCCCCCCHH	40.63	22322096
306	Phosphorylation	EGISDGATMKTFCGT CCCCCCCCCHHCCCC	25.40	22322096
306	O-linked_Glycosylation	EGISDGATMKTFCGT CCCCCCCCCHHCCCC	25.40	UniProtKB CARBOHYD
309	Phosphorylation	SDGATMKTFCGTPEY CCCCCCHHCCCCHHH	17.21	22322096
311	Glutathionylation	GATMKTFCGTPEYLA CCCCHHCCCCHHHHC	7.79	22555962
313	Phosphorylation	TMKTFCGTPEYLAPE CCHHCCCCHHHHCHH	17.71	22322096
313	O-linked_Glycosylation	TMKTFCGTPEYLAPE CCHHCCCCHHHHCHH	17.71	UniProtKB CARBOHYD
316	Phosphorylation	TFCGTPEYLAPEVLE HCCCCHHHHCHHHHC	14.90	22322096
327	Phosphorylation	EVLEDNDYGRAVDWW HHHCCCCCCCCHHHH	18.11	142487
335	Ubiquitination	GRAVDWWGLGVVMYE CCCHHHHHHHHHHHH	14.32	21890473
351	Phosphorylation	MCGRLPFYNQDHERL HHCCCCCCCCCHHHH	15.24	27642862
378	Ubiquitination	RTLSPEAKSLLAGLL CCCCHHHHHHHHHHH	39.72	21890473
378	Acetylation	RTLSPEAKSLLAGLL CCCCHHHHHHHHHHH	39.72	12437731
378	Ubiquitination	RTLSPEAKSLLAGLL CCCCHHHHHHHHHHH	39.72	21890473
379	Phosphorylation	TLSPEAKSLLAGLLK CCCHHHHHHHHHHHC	35.35	21712546
386	Acetylation	SLLAGLLKKDPKQRL HHHHHHHCCCHHHCC	61.24	25953088
401	Ubiquitination	GGGPSDAKEVMEHRF CCCCCCHHHHHHHCC	56.69	-
411	Phosphorylation	MEHRFFLSINWQDVV HHHCCEEEECHHHHH	14.55	28509920
427	Ubiquitination	KKLLPPFKPQVTSEV HHHCCCCCCCCCCCC	40.07	-
438	Phosphorylation	TSEVDTRYFDDEFTA CCCCCCCCCCCCCEE	17.29	131887
444	Phosphorylation	RYFDDEFTAQSITIT CCCCCCCEEEEEEEC	23.03	28060719
447	Phosphorylation	DDEFTAQSITITPPD CCCCEEEEEEECCCC	21.16	28450419
449	Phosphorylation	EFTAQSITITPPDRY CCEEEEEEECCCCCC	24.85	29255136
451	Phosphorylation	TAQSITITPPDRYDS EEEEEEECCCCCCCC	21.81	29255136
456	Phosphorylation	TITPPDRYDSLGLLE EECCCCCCCCCCCEE	19.77	28450419
458	Phosphorylation	TPPDRYDSLGLLELD CCCCCCCCCCCEEEC	18.53	30458377
468	Phosphorylation	LLELDQRTHFPQFSY CEEECCCCCCCCCCC	23.41	27080861
474	Phosphorylation	RTHFPQFSYSASIRE CCCCCCCCCCCCCCC	16.96	22322096
475	Phosphorylation	THFPQFSYSASIRE- CCCCCCCCCCCCCC-	15.00	22322096
476	Phosphorylation	HFPQFSYSASIRE-- CCCCCCCCCCCCC--	17.84	22322096
478	Phosphorylation	PQFSYSASIRE---- CCCCCCCCCCC----	19.08	22322096

Upstream regulatory proteins (kinases for phosphorylation sites, E3 ubiquitin ligases of ubiquitination sites, ...)

Modified Location	Modified Residue	Modification	Type of Upstream Proteins	Gene Name of Upstream Proteins	UniProt AC of Upstream Proteins	Sources
131	S	Phosphorylation	Kinase	CK2A1	P68400	PSP
309	T	Phosphorylation	Kinase	PDK1	Q15118	GPS
309	T	Phosphorylation	Kinase	PDK1	O15530	PSP
-	K	Ubiquitination	E3 ubiquitin ligase	TTC3	P53804	PMID:20059950
-	K	Ubiquitination	E3 ubiquitin ligase	TRAF6	Q9Y4K3	PMID:22199232
-	K	Ubiquitination	E3 ubiquitin ligase	TRIM13	O60858	PMID:21333377
-	K	Ubiquitination	E3 ubiquitin ligase	NEDD4	P46934	PMID:23195959
-	K	Ubiquitination	E3 ubiquitin ligase	SKP2	Q13309	PMID:22632973

Functions of PTM Sites

Modified Location	Modified Residue	Modification	Function	Reference
48	K	ubiquitylation	Ubiquitinated; undergoes both 'Lys-48'- and 'Lys-63'-linked polyubiquitination.	19713527
48	K	Phosphorylation	When fully phosphorylated and translocated into the nucleus, undergoes 'Lys-48'-polyubiquitination catalyzed by TTC3, leading to its degradation by the proteasome.	19713527
48	K	ubiquitylation	When fully phosphorylated and translocated into the nucleus, undergoes 'Lys-48'-polyubiquitination catalyzed by TTC3, leading to its degradation by the proteasome.	19713527
306	T	Phosphorylation	O-GlcNAcylation at Thr-306 and Thr-313 inhibits activating phosphorylation at Thr-309 via disrupting the interaction between AKT and PDK1.	-
309	T	Phosphorylation	O-GlcNAcylation at Thr-306 and Thr-313 inhibits activating phosphorylation at Thr-309 via disrupting the interaction between AKT and PDK1.	9512493
309	T	Phosphorylation	Phosphorylation on Thr-309 and Ser-474 is required for full activity.	9512493
313	T	Phosphorylation	O-GlcNAcylation at Thr-306 and Thr-313 inhibits activating phosphorylation at Thr-309 via disrupting the interaction between AKT and PDK1.	-
474	S	Phosphorylation	Phosphorylation on Thr-309 and Ser-474 is required for full activity.	15890450

Disease-associated PTM Sites based on SAP

* Distance = the distance between SAP position and PTM sites.

Oops, there are no SNP-PTM records of AKT2_HUMAN !!

Protein-Protein Interaction

Interacting Protein	Gene Name	Interaction Type	PPI Reference
DP13A_HUMAN	APPL1	physical	10490823
SH3R1_HUMAN	SH3RF1	physical	14504284
IKKA_HUMAN	CHUK	physical	12048203
TCL1A_HUMAN	TCL1A	physical	10983986
TCL1B_HUMAN	TCL1B	physical	10983986
MTCP1_HUMAN	MTCP1	physical	10983986
XIAP_HUMAN	XIAP	physical	14645242
SETB1_HUMAN	SETDB1	physical	17577629
TTC3_HUMAN	TTC3	physical	20059950
ESR1_HUMAN	ESR1	physical	11507039
SH3R1_HUMAN	SH3RF1	physical	17535800
VIME_HUMAN	VIM	physical	20856200
A4_HUMAN	APP	physical	21832049
HS90A_HUMAN	HSP90AA1	physical	22939624
M3K5_HUMAN	MAP3K5	physical	12697749
PLPL3_HUMAN	PNPLA3	physical	21988832
SNX27_HUMAN	SNX27	physical	21988832
APOA1_HUMAN	APOA1	physical	21988832
APOB_HUMAN	APOB	physical	21988832
CCL14_HUMAN	CCL14	physical	21988832
SPR2A_HUMAN	SPRR2A	physical	21988832
SRBS2_HUMAN	SORBS2	physical	21988832
NAMPT_HUMAN	NAMPT	physical	21988832
TMED2_HUMAN	TMED2	physical	21988832
OFUT1_HUMAN	POFUT1	physical	21988832
STEA4_HUMAN	STEAP4	physical	21988832
RPA2_HUMAN	POLR1B	physical	21988832
KPCZ_HUMAN	PRKCZ	physical	18353613
CLIP3_HUMAN	CLIP3	physical	19139280
PKHO1_HUMAN	PLEKHO1	physical	17942896
SNAI1_HUMAN	SNAI1	physical	22158034
H31_HUMAN	HIST1H3A	physical	22158034
4EBP1_HUMAN	EIF4EBP1	physical	26344197
GGA1_HUMAN	GGA1	physical	26344197
PK3CB_HUMAN	PIK3CB	physical	26344197
PK3CD_HUMAN	PIK3CD	physical	26344197
RPE_HUMAN	RPE	physical	26344197
UBE2O_HUMAN	UBE2O	physical	28514442
TPM2_HUMAN	TPM2	physical	28514442
USP9Y_HUMAN	USP9Y	physical	28514442
FAT3_HUMAN	FAT3	physical	28514442
UBB_HUMAN	UBB	physical	28514442
NSE4A_HUMAN	NSMCE4A	physical	28514442
PP2AA_HUMAN	PPP2CA	physical	27563096
GBB1_HUMAN	GNB1	physical	26895380
WDR26_HUMAN	WDR26	physical	26895380

Drug and Disease Associations

• Kegg Disease
• OMIM Disease
• : Note=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.
• 125853:
• 240900: Hypoinsulinemic hypoglycemia with hemihypertrophy (HIHGHH)
• Kegg Drug
• DrugBank
• There are no disease associations of PTM sites.

Related Literatures of Post-Translational Modification

Phosphorylation

"Quantitative phosphoproteomic analysis of T cell receptor signalingreveals 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).
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-447; THR-451; SER-474AND SER-478, AND MASS SPECTROMETRY.
PubMed: 19690332

"The E3 ligase TTC3 facilitates ubiquitination and degradation ofphosphorylated 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).
Cited for: UBIQUITINATION BY TTC3, PHOSPHORYLATION AT THR-309 AND SER-474, ANDMUTAGENESIS OF THR-309 AND SER-474.
PubMed: 20059950

"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).
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-126, AND MASSSPECTROMETRY.
PubMed: 18669648

"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).
Cited for: MUTAGENESIS OF THR-309 AND SER-474, AND PHOSPHORYLATION AT THR-309 ANDSER-474.
PubMed: 15890450

"Crystal structure of an activated Akt/protein kinase B ternarycomplex 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).
Cited for: X-RAY CRYSTALLOGRAPHY (1.60 ANGSTROMS) OF 146-467 IN COMPLEX WITHPHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER AND MANGANESE, ANDPHOSPHORYLATION AT THR-309.
PubMed: 12434148

"Activation of protein kinase B beta and gamma isoforms by insulin invivo 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).
Cited for: CHARACTERIZATION, AND PHOSPHORYLATION AT THR-309 BY PDPK1.
PubMed: 9512493