dbPTM

AAPK2_MOUSE - PTM Information in dbPTM

Basic Information of Protein

Overview of Protein Modification Sites with Functional and Structural Information
UniProt ID	AAPK2_MOUSE
UniProt AC	Q8BRK8
Protein Name	5'-AMP-activated protein kinase catalytic subunit alpha-2
Gene Name	Prkaa2 {ECO:0000312\|MGI:MGI:1336173}
Organism	Mus musculus (Mouse).
Sequence Length	552
Subcellular Localization	Cytoplasm. Nucleus. In response to stress, recruited by p53/TP53 to specific promoters.
Protein Description	Catalytic subunit of AMP-activated protein kinase (AMPK), an energy sensor protein kinase that plays a key role in regulating cellular energy metabolism. In response to reduction of intracellular ATP levels, AMPK activates energy-producing pathways and inhibits energy-consuming processes: inhibits protein, carbohydrate and lipid biosynthesis, as well as cell growth and proliferation. AMPK acts via direct phosphorylation of metabolic enzymes, and by longer-term effects via phosphorylation of transcription regulators. Also acts as a regulator of cellular polarity by remodeling the actin cytoskeleton; probably by indirectly activating myosin. Regulates lipid synthesis by phosphorylating and inactivating lipid metabolic enzymes such as ACACA, ACACB, GYS1, HMGCR and LIPE; regulates fatty acid and cholesterol synthesis by phosphorylating acetyl-CoA carboxylase (ACACA and ACACB) and hormone-sensitive lipase (LIPE) enzymes, respectively. Regulates insulin-signaling and glycolysis by phosphorylating IRS1, PFKFB2 and PFKFB3. Involved in insulin receptor/INSR internalization (By similarity). AMPK stimulates glucose uptake in muscle by increasing the translocation of the glucose transporter SLC2A4/GLUT4 to the plasma membrane, possibly by mediating phosphorylation of TBC1D4/AS160. Regulates transcription and chromatin structure by phosphorylating transcription regulators involved in energy metabolism such as CRTC2/TORC2, FOXO3, histone H2B, HDAC5, MEF2C, MLXIPL/ChREBP, EP300, HNF4A, p53/TP53, SREBF1, SREBF2 and PPARGC1A. Acts as a key regulator of glucose homeostasis in liver by phosphorylating CRTC2/TORC2, leading to CRTC2/TORC2 sequestration in the cytoplasm. In response to stress, phosphorylates 'Ser-36' of histone H2B (H2BS36ph), leading to promote transcription. Acts as a key regulator of cell growth and proliferation by phosphorylating TSC2, RPTOR and ATG1/ULK1: in response to nutrient limitation, negatively regulates the mTORC1 complex by phosphorylating RPTOR component of the mTORC1 complex and by phosphorylating and activating TSC2. In response to nutrient limitation, promotes autophagy by phosphorylating and activating ATG1/ULK1. AMPK also acts as a regulator of circadian rhythm by mediating phosphorylation of CRY1, leading to destabilize it. May regulate the Wnt signaling pathway by phosphorylating CTNNB1, leading to stabilize it. Also phosphorylates CFTR, EEF2K, KLC1, NOS3 and SLC12A1. Plays an important role in the differential regulation of pro-autophagy (composed of PIK3C3, BECN1, PIK3R4 and UVRAG or ATG14) and non-autophagy (composed of PIK3C3, BECN1 and PIK3R4) complexes, in response to glucose starvation. Can inhibit the non-autophagy complex by phosphorylating PIK3C3 and can activate the pro-autophagy complex by phosphorylating BECN1. [PubMed: 23332761]
Protein Sequence	MAEKQKHDGRVKIGHYVLGDTLGVGTFGKVKIGEHQLTGHKVAVKILNRQKIRSLDVVGKIKREIQNLKLFRHPHIIKLYQVISTPTDFFMVMEYVSGGELFDYICKHGRVEEVEARRLFQQILSAVDYCHRHMVVHRDLKPENVLLDAQMNAKIADFGLSNMMSDGEFLRTSCGSPNYAAPEVISGRLYAGPEVDIWSCGVILYALLCGTLPFDDEHVPTLFKKIRGGVFYIPDYLNRSVATLLMHMLQVDPLKRATIKDIREHEWFKQDLPSYLFPEDPSYDANVIDDEAVKEVCEKFECTESEVMNSLYSGDPQDQLAVAYHLIIDNRRIMNQASEFYLASSPPSGSFMDDSAMHIPPGLKPHPERMPPLIADSPKARCPLDALNTTKPKSLAVKKAKWHLGIRSQSKACDIMAEVYRAMKQLGFEWKVVNAYHLRVRRKNPVTGNYVKMSLQLYLVDSRSYLLDFKSIDDEVVEQRSGSSTPQRSCSAAGLHRARSSFDSSTAENHSLSGSLTGSLTGSTLSSASPRLGSHTMDFFEMCASLITALAR

Experimental Post-Translational Modification Sites

* ASA = Accessible Surface Area

Locations	Modification	Substrate Peptides & Secondary Structure	ASA (%)	Reference
16	Phosphorylation	GRVKIGHYVLGDTLG CCEEEEEEECCCCCC	7.67	26239621
21	Phosphorylation	GHYVLGDTLGVGTFG EEEECCCCCCCCCCC	24.50	26239621
26	Phosphorylation	GDTLGVGTFGKVKIG CCCCCCCCCCEEEEC	27.15	26239621
54	O-linked_Glycosylation	LNRQKIRSLDVVGKI HCHHHCCCCCHHHHH	32.18	30059200
60	Ubiquitination	RSLDVVGKIKREIQN CCCCHHHHHHHHHHC	33.18	22790023
69	Acetylation	KREIQNLKLFRHPHI HHHHHCCHHHCCHHH	53.80	22637201
161	Phosphorylation	KIADFGLSNMMSDGE HHHHCCHHHCCCCCC	24.06	22322096
165	Phosphorylation	FGLSNMMSDGEFLRT CCHHHCCCCCCHHHH	31.53	25159016
172	Phosphorylation	SDGEFLRTSCGSPNY CCCCHHHHCCCCCCC	30.43	25521595
173	Phosphorylation	DGEFLRTSCGSPNYA CCCHHHHCCCCCCCC	15.28	21082442
174	S-nitrosylation	GEFLRTSCGSPNYAA CCHHHHCCCCCCCCC	6.55	21278135
174	S-nitrosocysteine	GEFLRTSCGSPNYAA CCHHHHCCCCCCCCC	6.55	-
176	Phosphorylation	FLRTSCGSPNYAAPE HHHHCCCCCCCCCCH	17.82	21082442
179	Phosphorylation	TSCGSPNYAAPEVIS HCCCCCCCCCCHHHC	13.92	25619855
186	Phosphorylation	YAAPEVISGRLYAGP CCCCHHHCCCCCCCC	24.04	25777480
232	Phosphorylation	KIRGGVFYIPDYLNR HHCCCEECCHHHCCH	14.78	-
236	Phosphorylation	GVFYIPDYLNRSVAT CEECCHHHCCHHHHH	10.67	-
258	Phosphorylation	VDPLKRATIKDIREH CCCCCCCCHHHHHHC	32.37	28059163
310	Phosphorylation	TESEVMNSLYSGDPQ CHHHHHHHHHCCCHH	15.58	51459785
344	Phosphorylation	ASEFYLASSPPSGSF CCEEECCCCCCCCCC	40.56	23140645
345	Phosphorylation	SEFYLASSPPSGSFM CEEECCCCCCCCCCC	34.91	23140645
370	Oxidation	LKPHPERMPPLIADS CCCCHHHCCCCCCCC	3.70	17242355
377	Phosphorylation	MPPLIADSPKARCPL CCCCCCCCCCCCCCH	21.19	25521595
379	Ubiquitination	PLIADSPKARCPLDA CCCCCCCCCCCCHHH	53.03	22790023
470	Ubiquitination	RSYLLDFKSIDDEVV CCCCCCCCCCCHHHH	46.28	22790023
471	Phosphorylation	SYLLDFKSIDDEVVE CCCCCCCCCCHHHHH	31.10	26643407
481	Phosphorylation	DEVVEQRSGSSTPQR HHHHHHCCCCCCCCH	42.60	26643407
483	Phosphorylation	VVEQRSGSSTPQRSC HHHHCCCCCCCCHHH	32.08	26643407
484	Phosphorylation	VEQRSGSSTPQRSCS HHHCCCCCCCCHHHC	47.86	26643407
485	Phosphorylation	EQRSGSSTPQRSCSA HHCCCCCCCCHHHCH	25.74	16180547
489	Phosphorylation	GSSTPQRSCSAAGLH CCCCCCHHHCHHCHH	13.74	25521595
490	S-nitrosylation	SSTPQRSCSAAGLHR CCCCCHHHCHHCHHH	3.32	21278135
490	S-nitrosocysteine	SSTPQRSCSAAGLHR CCCCCHHHCHHCHHH	3.32	-
491	Phosphorylation	STPQRSCSAAGLHRA CCCCHHHCHHCHHHH	23.54	25521595
500	Phosphorylation	AGLHRARSSFDSSTA HCHHHHHHCCCCCCC	34.08	27742792
501	Phosphorylation	GLHRARSSFDSSTAE CHHHHHHCCCCCCCC	27.76	27742792
504	Phosphorylation	RARSSFDSSTAENHS HHHHCCCCCCCCCCC	27.81	23984901
505	Phosphorylation	ARSSFDSSTAENHSL HHHCCCCCCCCCCCC	33.22	23984901
506	Phosphorylation	RSSFDSSTAENHSLS HHCCCCCCCCCCCCC	41.78	27742792
511	Phosphorylation	SSTAENHSLSGSLTG CCCCCCCCCCCEEEC	35.49	23984901
513	Phosphorylation	TAENHSLSGSLTGSL CCCCCCCCCEEECCC	29.38	23984901
515	Phosphorylation	ENHSLSGSLTGSLTG CCCCCCCEEECCCCC	21.27	27742792
517	Phosphorylation	HSLSGSLTGSLTGST CCCCCEEECCCCCCC	26.82	27742792
519	Phosphorylation	LSGSLTGSLTGSTLS CCCEEECCCCCCCCC	19.95	23984901
521	Phosphorylation	GSLTGSLTGSTLSSA CEEECCCCCCCCCCC	30.68	26643407
523	Phosphorylation	LTGSLTGSTLSSASP EECCCCCCCCCCCCC	22.42	23984901
524	Phosphorylation	TGSLTGSTLSSASPR ECCCCCCCCCCCCCC	31.81	23984901

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
172	T	Phosphorylation	Kinase	PRKAA2	P54646	GPS
172	T	Phosphorylation	Kinase	CAMKK2	Q8C078	Uniprot
172	T	Phosphorylation	Kinase	STK11	Q9WTK7	GPS
491	S	Phosphorylation	Kinase	PRKD1	Q15139	PSP

Functions of PTM Sites

Modified Location	Modified Residue	Modification	Reference
172	T	Phosphorylation	15980064
Also phosphorylated at Thr-172 by CAMKK2; triggered by a rise in intracellular calcium ions, without detectable changes in the AMP/ATP ratio.
172	T	Phosphorylation	15980064
CAMKK1 can also phosphorylate Thr-172, but at much lower level.
172	T	Phosphorylation	15980064
Dephosphorylated by PPM1A and PPM1B at Thr-172 (mediated by STK11/LKB1) (By similarity).
172	T	Phosphorylation	15980064
Phosphorylated at Thr-172 by STK11/LKB1 in complex with STE20-related adapter-alpha (STRADA) pseudo kinase and CAB39.

Disease-associated PTM Sites based on SAP

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

Modified Location	Modification	Variant Position (Distance <= 10)	Residue Change	SAP	Related Disease	Reference
Oops, there are no SNP-PTM records of AAPK2_MOUSE !!

Protein-Protein Interaction

Interacting Protein	Gene Name	Interaction Type	PPI Reference	Domain-Domain Interactions
M3K7_MOUSE	Map3k7	physical	20615388

Drug and Disease Associations

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

Regulatory Network of AAPK2_MOUSE

Related Literatures of Post-Translational Modification

Phosphorylation
Reference	PubMed
"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-173 AND SER-500, ANDMASS SPECTROMETRY.	17242355 [Abstract]
"The kinase LKB1 mediates glucose homeostasis in liver and therapeuticeffects of metformin."; Shaw R.J., Lamia K.A., Vasquez D., Koo S.-H., Bardeesy N.,Depinho R.A., Montminy M., Cantley L.C.; Science 310:1642-1646(2005). Cited for: FUNCTION IN PHOSPHORYLATION OF CRTC2, AND PHOSPHORYLATION AT THR-172.	16308421 [Abstract]
"The Ca2+/calmodulin-dependent protein kinase kinases are AMP-activated protein kinase kinases."; Hurley R.L., Anderson K.A., Franzone J.M., Kemp B.E., Means A.R.,Witters L.A.; J. Biol. Chem. 280:29060-29066(2005). Cited for: PHOSPHORYLATION AT THR-172, AND ENZYME REGULATION.	15980064 [Abstract]

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