AKT2_MOUSE - PTM Information in dbPTM

Basic Information of Protein

• UniProt ID: AKT2_MOUSE
• UniProt AC: Q60823
• Protein Name: RAC-beta serine/threonine-protein kinase
• Gene Name: Akt2
• Organism: Mus musculus (Mouse).
• 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-te
• Protein Description: 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 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 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. 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. Phosphorylates CLK2 on 'Thr-343'..
• Protein Sequence: MNEVSVIKEGWLHKRGEYIKTWRPRYFLLKSDGSFIGYKERPEAPDQTLPPLNNFSVAECQLMKTERPRPNTFVIRCLQWTTVIERTFHVDSPDEREEWMRAIQMVANSLKQRGPGEDAMDYKCGSPSDSSTSEMMEVAVNKARAKVTMNDFDYLKLLGKGTFGKVILVREKATGRYYAMKILRKEVIIAKDEVAHTVTESRVLQNTRHPFLTALKYAFQTHDRLCFVMEYANGGELFFHLSRERVFTEDRARFYGAEIVSALEYLHSRDVVYRDIKLENLMLDKDGHIKITDFGLCKEGISDGATMKTFCGTPEYLAPEVLEDNDYGRAVDWWGLGVVMYEMMCGRLPFYNQDHERLFELILMEEIRFPRTLGPEAKSLLAGLLKKDPKQRLGGGPSDAKEVMEHRFFLSINWQDVVQKKLLPPFKPQVTSEVDTRYFDDEFTAQSITITPPDRYDSLDPLELDQRTHFPQFSYSASIRE

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	-
14	Acetylation	IKEGWLHKRGEYIKT EECCCCCCCCCCCCC	60.99	-
20	Acetylation	HKRGEYIKTWRPRYF CCCCCCCCCCCCEEE	40.93	-
31	Phosphorylation	PRYFLLKSDGSFIGY CEEEEECCCCCEECC	47.36	29472430
34	Phosphorylation	FLLKSDGSFIGYKER EEECCCCCEECCCCC	20.77	27180971
109	Phosphorylation	AIQMVANSLKQRGPG HHHHHHHHHHHHCCC	27.49	28725479
122	Phosphorylation	PGEDAMDYKCGSPSD CCCCCCCCCCCCCCC	8.62	29514104
126	Phosphorylation	AMDYKCGSPSDSSTS CCCCCCCCCCCCCHH	30.60	23527152
128	Phosphorylation	DYKCGSPSDSSTSEM CCCCCCCCCCCHHHH	52.39	28833060
128	O-linked_Glycosylation	DYKCGSPSDSSTSEM CCCCCCCCCCCHHHH	52.39	-
130	Phosphorylation	KCGSPSDSSTSEMME CCCCCCCCCHHHHHH	39.59	28833060
131	Phosphorylation	CGSPSDSSTSEMMEV CCCCCCCCHHHHHHH	40.73	28833060
131	O-linked_Glycosylation	CGSPSDSSTSEMMEV CCCCCCCCHHHHHHH	40.73	-
132	Phosphorylation	GSPSDSSTSEMMEVA CCCCCCCHHHHHHHH	32.43	28833060
133	Phosphorylation	SPSDSSTSEMMEVAV CCCCCCHHHHHHHHH	25.99	28833060
162	Phosphorylation	LKLLGKGTFGKVILV HHHHCCCCCCEEEEE	32.47	25338131
178	Phosphorylation	EKATGRYYAMKILRK ECCCCCCHHHHHHHC	10.00	-
255	Phosphorylation	TEDRARFYGAEIVSA CHHHHHHHHHHHHHH	15.18	51459247
261	Phosphorylation	FYGAEIVSALEYLHS HHHHHHHHHHHHHHH	32.56	51459255
265	Phosphorylation	EIVSALEYLHSRDVV HHHHHHHHHHHCCCE	15.57	51459263
302	Phosphorylation	GLCKEGISDGATMKT CCCCCCCCCCCCCHH	40.63	30815027
306	O-linked_Glycosylation	EGISDGATMKTFCGT CCCCCCCCCHHCCCC	25.40	-
306	Phosphorylation	EGISDGATMKTFCGT CCCCCCCCCHHCCCC	25.40	22322096
309	Phosphorylation	SDGATMKTFCGTPEY CCCCCCHHCCCCHHH	17.21	7913
313	O-linked_Glycosylation	TMKTFCGTPEYLAPE CCHHCCCCHHHHCHH	17.71	-
313	Phosphorylation	TMKTFCGTPEYLAPE CCHHCCCCHHHHCHH	17.71	22322096
316	Phosphorylation	TFCGTPEYLAPEVLE HCCCCHHHHCHHHHC	14.90	11445557
327	Phosphorylation	EVLEDNDYGRAVDWW HHHCCCCCCCCHHHH	18.11	141681
438	Phosphorylation	TSEVDTRYFDDEFTA CCCCCCCCCCCCCEE	17.29	25619855
444	Phosphorylation	RYFDDEFTAQSITIT CCCCCCCEEEEEEEC	23.03	25619855
447	Phosphorylation	DDEFTAQSITITPPD CCCCEEEEEEECCCC	21.16	25619855
449	Phosphorylation	EFTAQSITITPPDRY CCEEEEEEECCCCCC	24.85	25619855
451	Phosphorylation	TAQSITITPPDRYDS EEEEEEECCCCCCCC	21.81	27087446
456	Phosphorylation	TITPPDRYDSLDPLE EECCCCCCCCCCCCC	19.77	25619855
458	Phosphorylation	TPPDRYDSLDPLELD CCCCCCCCCCCCCCC	26.24	25619855
468	Phosphorylation	PLELDQRTHFPQFSY CCCCCCCCCCCCCCC	23.41	23737553
474	Phosphorylation	RTHFPQFSYSASIRE CCCCCCCCCCCCCCC	16.96	22322096
475	Phosphorylation	THFPQFSYSASIRE- CCCCCCCCCCCCCC-	15.00	26239621
476	Phosphorylation	HFPQFSYSASIRE-- CCCCCCCCCCCCC--	17.84	26239621
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
309	T	Phosphorylation	Kinase	PDPK1	Q9Z2A0	Uniprot
-	K	Ubiquitination	E3 ubiquitin ligase	Ttc3	O88196	PMID:22199232

Functions of PTM Sites

Modified Location	Modified Residue	Modification	Function	Reference
48	K	ubiquitylation	Ubiquitinated; undergoes both 'Lys-48'- and 'Lys-63'-linked polyubiquitination.	-
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 (By similarity).	-
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 (By similarity).	-
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.	-
309	T	Phosphorylation	Phosphorylation on Thr-309 and Ser-474 is required for full activity.	-
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.	-

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_MOUSE !!

Protein-Protein Interaction

Interacting Protein	Gene Name	Interaction Type	PPI Reference
BTBDA_MOUSE	Btbd10	physical	18160256
KCD20_MOUSE	Kctd20	physical	24156551
CLIP3_MOUSE	Clip3	physical	19139280
GSK3A_MOUSE	Gsk3a	physical	20576936
GSK3B_MOUSE	Gsk3b	physical	20576936
TISD_HUMAN	ZFP36L2	physical	26496610
BRNP1_HUMAN	BRINP1	physical	26496610
DRC1_HUMAN	DRC1	physical	26496610

Drug and Disease Associations

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