AKT1_MOUSE - PTM Information in dbPTM

Basic Information of Protein

• UniProt ID: AKT1_MOUSE
• UniProt AC: P31750
• Protein Name: RAC-alpha serine/threonine-protein kinase
• Gene Name: Akt1
• Organism: Mus musculus (Mouse).
• Sequence Length: 480
• Subcellular Localization: Cytoplasm . Nucleus . Cell membrane. Nucleus after activation by integrin-linked protein kinase 1 (ILK1) (By similarity). Nuclear translocation is enhanced by interaction with TCL1A. Phosphorylation on Tyr-176 by TNK2 results in its localization to t
• Protein Description: 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 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. 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 (By similarity). Phosphorylates RAF1 at 'Ser-259' and negatively regulates its 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..
• Protein Sequence: MNDVAIVKEGWLHKRGEYIKTWRPRYFLLKNDGTFIGYKERPQDVDQRESPLNNFSVAQCQLMKTERPRPNTFIIRCLQWTTVIERTFHVETPEEREEWATAIQTVADGLKRQEEETMDFRSGSPSDNSGAEEMEVSLAKPKHRVTMNEFEYLKLLGKGTFGKVILVKEKATGRYYAMKILKKEVIVAKDEVAHTLTENRVLQNSRHPFLTALKYSFQTHDRLCFVMEYANGGELFFHLSRERVFSEDRARFYGAEIVSALDYLHSEKNVVYRDLKLENLMLDKDGHIKITDFGLCKEGIKDGATMKTFCGTPEYLAPEVLEDNDYGRAVDWWGLGVVMYEMMCGRLPFYNQDHEKLFELILMEEIRFPRTLGPEAKSLLSGLLKKDPTQRLGGGSEDAKEIMQHRFFANIVWQDVYEKKLSPPFKPQVTSETDTRYFDEEFTAQMITITPPDQDDSMECVDSERRPHFPQFSYSASGTA

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
14	Acetylation	VKEGWLHKRGEYIKT EECCCCCCCCCCCCC	60.99	-
20	Acetylation	HKRGEYIKTWRPRYF CCCCCCCCCCCCEEE	40.93	-
30	Ubiquitination	RPRYFLLKNDGTFIG CCEEEEECCCCCEEE	55.96	22790023
50	Phosphorylation	QDVDQRESPLNNFSV CCCCCCCCCCCCCCH	36.56	25521595
60	Glutathionylation	NNFSVAQCQLMKTER CCCCHHHHHHHCCCC	2.12	24333276
65	Phosphorylation	AQCQLMKTERPRPNT HHHHHHCCCCCCCCE	24.22	26026062
72	Phosphorylation	TERPRPNTFIIRCLQ CCCCCCCEEEEEHHE	20.92	26026062
117	Phosphorylation	LKRQEEETMDFRSGS HHHHHHHHCCCCCCC	25.89	15634149
122	Phosphorylation	EETMDFRSGSPSDNS HHHCCCCCCCCCCCC	43.55	27087446
124	Phosphorylation	TMDFRSGSPSDNSGA HCCCCCCCCCCCCCC	23.60	27087446
126	Phosphorylation	DFRSGSPSDNSGAEE CCCCCCCCCCCCCCC	51.63	27087446
126	O-linked_Glycosylation	DFRSGSPSDNSGAEE CCCCCCCCCCCCCCC	51.63	-
129	Phosphorylation	SGSPSDNSGAEEMEV CCCCCCCCCCCCEEE	44.35	27087446
129	O-linked_Glycosylation	SGSPSDNSGAEEMEV CCCCCCCCCCCCEEE	44.35	-
134	Oxidation	DNSGAEEMEVSLAKP CCCCCCCEEEECCCC	4.66	17242355
137	Phosphorylation	GAEEMEVSLAKPKHR CCCCEEEECCCCCCE	14.87	25619855
160	Phosphorylation	LKLLGKGTFGKVILV HHHHCCCCCCEEEEE	32.47	25338131
176	Phosphorylation	EKATGRYYAMKILKK ECCCCCCCHHHHHCC	10.00	20333297
179	Acetylation	TGRYYAMKILKKEVI CCCCCHHHHHCCEEE	36.39	22826441
195	Phosphorylation	AKDEVAHTLTENRVL ECHHHHHHHHHCCCC	26.15	25338131
276	Ubiquitination	NVVYRDLKLENLMLD CEECCCCCHHHEEEC	59.03	22790023
276	Acetylation	NVVYRDLKLENLMLD CEECCCCCHHHEEEC	59.03	23236377
305	Phosphorylation	EGIKDGATMKTFCGT CCCCCCCCCCCCCCC	25.40	22322096
305	O-linked_Glycosylation	EGIKDGATMKTFCGT CCCCCCCCCCCCCCC	25.40	-
308	Phosphorylation	KDGATMKTFCGTPEY CCCCCCCCCCCCHHH	17.21	22322096
308	O-linked_Glycosylation	KDGATMKTFCGTPEY CCCCCCCCCCCCHHH	17.21	26866564
312	Phosphorylation	TMKTFCGTPEYLAPE CCCCCCCCHHHHCHH	17.71	22322096
312	O-linked_Glycosylation	TMKTFCGTPEYLAPE CCCCCCCCHHHHCHH	17.71	-
315	Phosphorylation	TFCGTPEYLAPEVLE CCCCCHHHHCHHHHC	14.90	22322096
326	Phosphorylation	EVLEDNDYGRAVDWW HHHCCCCCCCCHHHH	18.11	22817900
350	Nitration	MCGRLPFYNQDHEKL HHCCCCCCCCCHHHH	15.24	-
430	O-linked_Glycosylation	PPFKPQVTSETDTRY CCCCCCCCCCCCCCC	18.65	26866564
437	Phosphorylation	TSETDTRYFDEEFTA CCCCCCCCCCHHCEE	19.92	27087446
443	Phosphorylation	RYFDEEFTAQMITIT CCCCHHCEEEEEEEC	21.18	23649490
448	Phosphorylation	EFTAQMITITPPDQD HCEEEEEEECCCCCC	17.29	23649490
450	Phosphorylation	TAQMITITPPDQDDS EEEEEEECCCCCCCC	21.81	10722653
473	Phosphorylation	RPHFPQFSYSASGTA CCCCCCCCCCCCCCC	16.96	20691662
473	O-linked_Glycosylation	RPHFPQFSYSASGTA CCCCCCCCCCCCCCC	16.96	-
474	Phosphorylation	PHFPQFSYSASGTA- CCCCCCCCCCCCCC-	15.00	22322096
475	Phosphorylation	HFPQFSYSASGTA-- CCCCCCCCCCCCC--	18.11	22322096
477	Phosphorylation	PQFSYSASGTA---- CCCCCCCCCCC----	30.64	25266776
479	O-linked_Glycosylation	FSYSASGTA------ CCCCCCCCC------	27.05	26866564
479	Phosphorylation	FSYSASGTA------ CCCCCCCCC------	27.05	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
176	Y	Phosphorylation	Kinase	ACK	O54967	PSP
308	T	Phosphorylation	Kinase	IKKE	Q9R0T8	Uniprot
308	T	Phosphorylation	Kinase	TBK1	Q9WUN2	Uniprot
308	T	Phosphorylation	Kinase	MAPK3	Q63844	GPS
308	T	Phosphorylation	Kinase	MAPK14	P47811	GPS
308	T	Phosphorylation	Kinase	PDK1	Q9Z2A0	PSP
308	T	Phosphorylation	Kinase	PDK1	O15530	PSP
315	Y	Phosphorylation	Kinase	SRC64	-	PhosphoELM
315	Y	Phosphorylation	Kinase	SRC	P05480	PSP
326	Y	Phosphorylation	Kinase	SRC64	-	PhosphoELM
326	Y	Phosphorylation	Kinase	SRC	P05480	PSP
450	T	Phosphorylation	Kinase	MTOR	Q9JLN9	Uniprot
473	S	Phosphorylation	Kinase	MTOR	Q9JLN9	Uniprot
473	S	Phosphorylation	Kinase	PIK3C2A	O00443	PSP
473	S	Phosphorylation	Kinase	MTOR	P42345	PSP
473	S	Phosphorylation	Kinase	MAPK14	P47811	GPS
473	S	Phosphorylation	Kinase	PRKCB	P68404	GPS
473	S	Phosphorylation	Kinase	PRKCA	P20444	GPS
473	S	Phosphorylation	Kinase	ILK	Q13418	PSP
473	S	Phosphorylation	Kinase	TBK1	Q9WUN2	Uniprot
473	S	Phosphorylation	Kinase	PRKCB ISOFORM BETA-I	-	GPS
473	S	Phosphorylation	Kinase	IKKE	Q9R0T8	Uniprot
473	S	Phosphorylation	Kinase	AKT1	P31750	PSP
-	K	Ubiquitination	E3 ubiquitin ligase	Stub1	Q9WUD1	PMID:22199232
-	K	Ubiquitination	E3 ubiquitin ligase	Traf6	P70196	PMID:22199232
-	K	Ubiquitination	E3 ubiquitin ligase	Ttc3	O88196	PMID:22199232

Functions of PTM Sites

Modified Location	Modified Residue	Modification	Function	Reference
14	K	Acetylation	Deacetylated at Lys-14 and Lys-20 by SIRT1.	-
14	K	Acetylation	Acetylated on Lys-14 and Lys-20 by the histone acetyltransferases EP300 and KAT2B.	-
20	K	Acetylation	Acetylated on Lys-14 and Lys-20 by the histone acetyltransferases EP300 and KAT2B.	-
20	K	Acetylation	Deacetylated at Lys-14 and Lys-20 by SIRT1.	-
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.	20333297
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.	20333297
48	K	ubiquitylation	Ubiquitinated; undergoes both 'Lys-48'- and 'Lys-63'-linked polyubiquitination.	20333297
284	K	ubiquitylation	Phosphorylated, undergoes 'Lys-48'-linked polyubiquitination preferentially at Lys-284 catalyzed by MUL1, leading to its proteasomal degradation.	20333297
284	K	Phosphorylation	Phosphorylated, undergoes 'Lys-48'-linked polyubiquitination preferentially at Lys-284 catalyzed by MUL1, leading to its proteasomal degradation.	20333297
305	T	Phosphorylation	O-GlcNAcylation at Thr-305 and Thr-312 inhibits activating phosphorylation at Thr-308 via disrupting the interaction between AKT1 and PDPK1.	-
308	T	Phosphorylation	This phosphorylated form localizes to the plasma membrane, where it is targeted by PDPK1 and PDPK2 for further phosphorylations on Thr-308 and Ser-473 leading to its activation.	15753085
308	T	Phosphorylation	Ser-473 phosphorylation by mTORC2 favors Thr-308 phosphorylation by PDPK1.	15753085
308	T	Phosphorylation	Phosphorylation on Thr-308, Ser-473 and Tyr-474 is required for full activity.	15753085
308	T	Phosphorylation	Phosphorylated at Thr-308 and Ser-473 by IKBKE and TBK1.	15753085
308	T	Phosphorylation	O-GlcNAcylation at Thr-305 and Thr-312 inhibits activating phosphorylation at Thr-308 via disrupting the interaction between AKT1 and PDPK1.	15753085
308	T	Phosphorylation	Dephosphorylated at Thr-308 and Ser-473 by PP2A phosphatase.	15753085
312	T	Phosphorylation	O-GlcNAcylation at Thr-305 and Thr-312 inhibits activating phosphorylation at Thr-308 via disrupting the interaction between AKT1 and PDPK1.	-
473	S	Phosphorylation	This phosphorylated form localizes to the plasma membrane, where it is targeted by PDPK1 and PDPK2 for further phosphorylations on Thr-308 and Ser-473 leading to its activation.	12783884
473	S	Phosphorylation	Ser-473 phosphorylation is enhanced by signaling through activated FLT3.	12783884
473	S	Phosphorylation	Ser-473 phosphorylation by mTORC2 favors Thr-308 phosphorylation by PDPK1.	12783884
473	S	Phosphorylation	Ser-473 is dephosphorylated by PHLPP (By similarity).	12783884
473	S	Phosphorylation	Ser-473 is dephosphorylated by CPPED1, leading to termination of signaling (By similarity).	12783884
473	S	Phosphorylation	Phosphorylation on Thr-308, Ser-473 and Tyr-474 is required for full activity.	12783884
473	S	Phosphorylation	Phosphorylated at Thr-308 and Ser-473 by IKBKE and TBK1.	12783884
473	S	Phosphorylation	O-GlcNAcylation at Ser-473 also probably interferes with phosphorylation at this site (By similarity).	12783884
473	S	Phosphorylation	Dephosphorylated at Thr-308 and Ser-473 by PP2A phosphatase.	12783884

Disease-associated PTM Sites based on SAP

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

Oops, there are no SNP-PTM records of AKT1_MOUSE !!

Protein-Protein Interaction

Interacting Protein	Gene Name	Interaction Type	PPI Reference
B2L11_HUMAN	BCL2L11	physical	16282323
BTBDA_MOUSE	Btbd10	physical	18160256
H2B1C_MOUSE	Hist1h2bc	physical	11435472
H2B2B_MOUSE	Hist2h2bb	physical	9582374
AKT1_MOUSE	Akt1	physical	7891724
PRGC1_MOUSE	Ppargc1a	physical	17554339
HS90B_MOUSE	Hsp90ab1	physical	10995457
HS90A_MOUSE	Hsp90aa1	physical	10995457
KCD20_MOUSE	Kctd20	physical	24156551
SOX2_MOUSE	Sox2	physical	25042802
CTND1_MOUSE	Ctnnd1	physical	17993462
GRDN_MOUSE	Ccdc88a	physical	15753085
HS90A_MOUSE	Hsp90aa1	physical	18566586
HD_HUMAN	HTT	physical	15843398
GSK3A_MOUSE	Gsk3a	physical	18851840
GSK3B_MOUSE	Gsk3b	physical	18851840
2ABB_MOUSE	Ppp2r2b	physical	16051150
PP2AA_MOUSE	Ppp2ca	physical	16051150
ARRB1_MOUSE	Arrb1	physical	16051150
ARRB2_MOUSE	Arrb2	physical	16051150
SRC_MOUSE	Src	physical	19122674
ARRB2_MOUSE	Arrb2	physical	19122674
CLIP3_MOUSE	Clip3	physical	19139280
GSK3A_MOUSE	Gsk3a	physical	20576936
GSK3B_MOUSE	Gsk3b	physical	20576936
AKT2_MOUSE	Akt2	genetic	15545269
MK14_MOUSE	Mapk14	physical	17015449
HSPB2_MOUSE	Hspb2	physical	17015449
MAPK2_MOUSE	Mapkapk2	physical	17015449
HSPB1_MOUSE	Hspb1	physical	12740362
GSK3A_MOUSE	Gsk3a	physical	21084607
GSK3B_MOUSE	Gsk3b	physical	21084607
HS90A_HUMAN	HSP90AA1	physical	19662498

Drug and Disease Associations

• Kegg Drug
• DrugBank
• There are no disease associations of PTM sites.

Related Literatures of Post-Translational Modification

O-linked Glycosylation

"Phosphoinositide signalling links O-GlcNAc transferase to insulinresistance.";
Yang X., Ongusaha P.P., Miles P.D., Havstad J.C., Zhang F., So W.V.,Kudlow J.E., Michell R.H., Olefsky J.M., Field S.J., Evans R.M.;
Nature 451:964-969(2008).
Cited for: FUNCTION, GLYCOSYLATION AT SER-473, AND PHOSPHORYLATION AT THR-308.
PubMed: 18288188

"O-GlcNAc modulation at Akt1 Ser473 correlates with apoptosis ofmurine pancreatic beta cells.";
Kang E.S., Han D., Park J., Kwak T.K., Oh M.A., Lee S.A., Choi S.,Park Z.Y., Kim Y., Lee J.W.;
Exp. Cell Res. 314:2238-2248(2008).
Cited for: GLYCOSYLATION AT SER-473.
PubMed: 18570920

Phosphorylation

"Solid tumor proteome and phosphoproteome analysis by high resolutionmass spectrometry.";
Zanivan S., Gnad F., Wickstroem S.A., Geiger T., Macek B., Cox J.,Faessler R., Mann M.;
J. Proteome Res. 7:5314-5326(2008).
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-129, AND MASSSPECTROMETRY.
PubMed: 19367708

"Large-scale phosphorylation analysis of mouse liver.";
Villen J., Beausoleil S.A., Gerber S.A., Gygi S.P.;
Proc. Natl. Acad. Sci. U.S.A. 104:1488-1493(2007).
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-124; SER-126 ANDSER-129, AND MASS SPECTROMETRY.
PubMed: 17242355

"Ack1 mediated AKT/PKB tyrosine 176 phosphorylation regulates itsactivation.";
Mahajan K., Coppola D., Challa S., Fang B., Chen Y.A., Zhu W.,Lopez A.S., Koomen J., Engelman R.W., Rivera C., Muraoka-Cook R.S.,Cheng J.Q., Schoenbrunn E., Sebti S.M., Earp H.S., Mahajan N.P.;
PLoS ONE 5:E9646-E9646(2010).
Cited for: FUNCTION, SUBCELLULAR LOCATION, PHOSPHORYLATION AT TYR-176; THR-308AND SER-473, MUTAGENESIS OF TYR-176, AND INTERACTION WITH TNK2.
PubMed: 20333297

"mTORC2 can associate with ribosomes to promote cotranslationalphosphorylation and stability of nascent Akt polypeptide.";
Oh W.J., Wu C.C., Kim S.J., Facchinetti V., Julien L.A., Finlan M.,Roux P.P., Su B., Jacinto E.;
EMBO J. 29:3939-3951(2010).
Cited for: PHOSPHORYLATION AT THR-450.
PubMed: 21045808

"Phosphoinositide signalling links O-GlcNAc transferase to insulinresistance.";
Yang X., Ongusaha P.P., Miles P.D., Havstad J.C., Zhang F., So W.V.,Kudlow J.E., Michell R.H., Olefsky J.M., Field S.J., Evans R.M.;
Nature 451:964-969(2008).
Cited for: FUNCTION, GLYCOSYLATION AT SER-473, AND PHOSPHORYLATION AT THR-308.
PubMed: 18288188

"A novel protein kinase B (PKB)/AKT-binding protein enhances PKBkinase activity and regulates DNA synthesis.";
Anai M., Shojima N., Katagiri H., Ogihara T., Sakoda H., Onishi Y.,Ono H., Fujishiro M., Fukushima Y., Horike N., Viana A., Kikuchi M.,Noguchi N., Takahashi S., Takata K., Oka Y., Uchijima Y., Kurihara H.,Asano T.;
J. Biol. Chem. 280:18525-18535(2005).
Cited for: INTERACTION WITH CCDC88A, AND PHOSPHORYLATION AT THR-308 AND SER-473.
PubMed: 15753085