dbPTM

AAPK2_HUMAN - PTM Information in dbPTM

Basic Information of Protein

Overview of Protein Modification Sites with Functional and Structural Information
UniProt ID	AAPK2_HUMAN
UniProt AC	P54646
Protein Name	5'-AMP-activated protein kinase catalytic subunit alpha-2
Gene Name	PRKAA2
Organism	Homo sapiens (Human).
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. [PubMed: 25687571 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 (By similarity]
Protein Sequence	MAEKQKHDGRVKIGHYVLGDTLGVGTFGKVKIGEHQLTGHKVAVKILNRQKIRSLDVVGKIKREIQNLKLFRHPHIIKLYQVISTPTDFFMVMEYVSGGELFDYICKHGRVEEMEARRLFQQILSAVDYCHRHMVVHRDLKPENVLLDAHMNAKIADFGLSNMMSDGEFLRTSCGSPNYAAPEVISGRLYAGPEVDIWSCGVILYALLCGTLPFDDEHVPTLFKKIRGGVFYIPEYLNRSVATLLMHMLQVDPLKRATIKDIREHEWFKQDLPSYLFPEDPSYDANVIDDEAVKEVCEKFECTESEVMNSLYSGDPQDQLAVAYHLIIDNRRIMNQASEFYLASSPPSGSFMDDSAMHIPPGLKPHPERMPPLIADSPKARCPLDALNTTKPKSLAVKKAKWHLGIRSQSKPYDIMAEVYRAMKQLDFEWKVVNAYHLRVRRKNPVTGNYVKMSLQLYLVDNRSYLLDFKSIDDEVVEQRSGSSTPQRSCSAAGLHRPRSSFDSTTAESHSLSGSLTGSLTGSTLSSVSPRLGSHTMDFFEMCASLITTLAR

Experimental Post-Translational Modification Sites

* ASA = Accessible Surface Area

Locations	Modification	Substrate Peptides & Secondary Structure	ASA (%)	Reference
21	Phosphorylation	GHYVLGDTLGVGTFG EEEECCCCCCCCCCC	24.50	28857561
26	Phosphorylation	GDTLGVGTFGKVKIG CCCCCCCCCCEEEEC	27.15	28857561
38	Phosphorylation	KIGEHQLTGHKVAVK EECCEECCCCEEHHH	30.58	28857561
41	Ubiquitination	EHQLTGHKVAVKILN CEECCCCEEHHHHHC	32.98	29967540
45	Ubiquitination	TGHKVAVKILNRQKI CCCEEHHHHHCHHHC	31.57	29967540
54	Phosphorylation	LNRQKIRSLDVVGKI HCHHHCCCCCHHHHH	32.18	28857561
64	Ubiquitination	VVGKIKREIQNLKLF HHHHHHHHHHCCHHH	43.88	21963094
69	Ubiquitination	KREIQNLKLFRHPHI HHHHHCCHHHCCHHH	53.80	24816145
69	Acetylation	KREIQNLKLFRHPHI HHHHHCCHHHCCHHH	53.80	23236377
69	Malonylation	KREIQNLKLFRHPHI HHHHHCCHHHCCHHH	53.80	26320211
125	Phosphorylation	RLFQQILSAVDYCHR HHHHHHHHHHHHHHH	28.07	23401153
141	Ubiquitination	MVVHRDLKPENVLLD CEECCCCCHHHEEEE	55.35	-
154	Ubiquitination	LDAHMNAKIADFGLS EEHHHCHHHHCCCHH	33.16	21963094
161	Phosphorylation	KIADFGLSNMMSDGE HHHCCCHHHCCCCCC	24.06	22322096
165	Phosphorylation	FGLSNMMSDGEFLRT CCHHHCCCCCCHHHH	31.53	26657352
172	Phosphorylation	SDGEFLRTSCGSPNY CCCCHHHHCCCCCCC	30.43	22322096
173	Phosphorylation	DGEFLRTSCGSPNYA CCCHHHHCCCCCCCC	15.28	22322096
176	Phosphorylation	FLRTSCGSPNYAAPE HHHHCCCCCCCCCCH	17.82	22322096
179	Phosphorylation	TSCGSPNYAAPEVIS HCCCCCCCCCCHHHC	13.92	26552605
186	Phosphorylation	YAAPEVISGRLYAGP CCCCHHHCCCCCCCC	24.04	26552605
227	Methylation	PTLFKKIRGGVFYIP HHHHHHHHCCEECCH	44.70	-
232	Phosphorylation	KIRGGVFYIPEYLNR HHHCCEECCHHHHCH	17.11	46163105
258	Phosphorylation	VDPLKRATIKDIREH CCCCCCCCHHHHHHC	32.37	-
260	Ubiquitination	PLKRATIKDIREHEW CCCCCCHHHHHHCHH	42.63	-
269	Ubiquitination	IREHEWFKQDLPSYL HHHCHHHHCCCHHHC	43.93	29967540
283	Phosphorylation	LFPEDPSYDANVIDD CCCCCCCCCCCCCCH	25.18	27642862
324	Phosphorylation	QDQLAVAYHLIIDNR HHHHHHHHHHHHCCH	7.20	20068231
344	Phosphorylation	ASEFYLASSPPSGSF CCEEECCCCCCCCCC	40.56	22210691
345	Phosphorylation	SEFYLASSPPSGSFM CEEECCCCCCCCCCC	34.91	28348404
348	Phosphorylation	YLASSPPSGSFMDDS ECCCCCCCCCCCCCC	50.91	29449344
350	Phosphorylation	ASSPPSGSFMDDSAM CCCCCCCCCCCCCCC	23.03	29449344
377	Phosphorylation	MPPLIADSPKARCPL CCCCCCCCCCCCCCH	21.19	19413330
389	Phosphorylation	CPLDALNTTKPKSLA CCHHHCCCCCCCHHH	36.73	28857561
391	Ubiquitination	LDALNTTKPKSLAVK HHHCCCCCCCHHHHC	48.70	29967540
393	Ubiquitination	ALNTTKPKSLAVKKA HCCCCCCCHHHHCHH	60.71	29967540
401	Sumoylation	SLAVKKAKWHLGIRS HHHHCHHEEECCCCC	43.98	-
401	Ubiquitination	SLAVKKAKWHLGIRS HHHHCHHEEECCCCC	43.98	-
401	Sumoylation	SLAVKKAKWHLGIRS HHHHCHHEEECCCCC	43.98	-
436	Phosphorylation	EWKVVNAYHLRVRRK CEEEEEEEEEEEEEC	9.00	116218607
481	Phosphorylation	DEVVEQRSGSSTPQR HHHHHHCCCCCCCCC	42.60	22199227
483	Phosphorylation	VVEQRSGSSTPQRSC HHHHCCCCCCCCCCC	32.08	22199227
484	Phosphorylation	VEQRSGSSTPQRSCS HHHCCCCCCCCCCCC	47.86	22199227
485	Phosphorylation	EQRSGSSTPQRSCSA HHCCCCCCCCCCCCC	25.74	16180553
489	Phosphorylation	GSSTPQRSCSAAGLH CCCCCCCCCCCCCCC	13.74	113311033
491	Phosphorylation	STPQRSCSAAGLHRP CCCCCCCCCCCCCCC	23.54	26657352
500	Phosphorylation	AGLHRPRSSFDSTTA CCCCCCCCCCCCCCC	37.73	18691976
501	Phosphorylation	GLHRPRSSFDSTTAE CCCCCCCCCCCCCCC	34.06	30576142
504	Phosphorylation	RPRSSFDSTTAESHS CCCCCCCCCCCCCCC	26.16	27251275
505	Phosphorylation	PRSSFDSTTAESHSL CCCCCCCCCCCCCCC	31.69	26657352
506	Phosphorylation	RSSFDSTTAESHSLS CCCCCCCCCCCCCCC	32.17	27251275
509	Phosphorylation	FDSTTAESHSLSGSL CCCCCCCCCCCCCEE	18.86	28857561
511	Phosphorylation	STTAESHSLSGSLTG CCCCCCCCCCCEEEC	33.25	28857561
513	Phosphorylation	TAESHSLSGSLTGSL CCCCCCCCCEEECCC	29.38	27251275
515	Phosphorylation	ESHSLSGSLTGSLTG CCCCCCCEEECCCCC	21.27	28857561
517	Phosphorylation	HSLSGSLTGSLTGST CCCCCEEECCCCCCC	26.82	27251275
519	Phosphorylation	LSGSLTGSLTGSTLS CCCEEECCCCCCCHH	19.95	27251275
521	Phosphorylation	GSLTGSLTGSTLSSV CEEECCCCCCCHHHC	30.68	26471730
524	Phosphorylation	TGSLTGSTLSSVSPR ECCCCCCCHHHCCCC	31.81	9390351
527	Phosphorylation	LTGSTLSSVSPRLGS CCCCCHHHCCCCCCC	29.72	46163093
529	Phosphorylation	GSTLSSVSPRLGSHT CCCHHHCCCCCCCCH	13.27	30576142
534	Phosphorylation	SVSPRLGSHTMDFFE HCCCCCCCCHHHHHH	22.00	46163099

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	CAMKK2	Q96RR4	Uniprot
172	T	Phosphorylation	Kinase	MAP3K7	O43318	GPS
172	T	Phosphorylation	Kinase	STK11	Q15831	GPS
172	T	Phosphorylation	Kinase	AMPK-FAMILY	-	GPS
172	T	Phosphorylation	Kinase	AMPK_GROUP	-	PhosphoELM
436	Y	Phosphorylation	Kinase	FYN	P06241	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).
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_HUMAN !!

Protein-Protein Interaction

Interacting Protein	Gene Name	Interaction Type	PPI Reference
AAKB2_HUMAN	PRKAB2	physical	20562859
AAKG1_HUMAN	PRKAG1	physical	20562859
MLF2_HUMAN	MLF2	physical	20562859
AAPK1_HUMAN	PRKAA1	physical	20562859
STIM2_HUMAN	STIM2	physical	20562859
SPD2A_HUMAN	SH3PXD2A	physical	20562859
STIM1_HUMAN	STIM1	physical	20562859
GYS1_HUMAN	GYS1	physical	20562859
AAKG2_HUMAN	PRKAG2	physical	20562859
C170B_HUMAN	CEP170B	physical	20562859
MAST3_HUMAN	MAST3	physical	20562859
M3K5_HUMAN	MAP3K5	physical	20562859
M3K6_HUMAN	MAP3K6	physical	20562859
BI2L1_HUMAN	BAIAP2L1	physical	20562859
GLYG_HUMAN	GYG1	physical	20562859
PK3CG_HUMAN	PIK3CG	physical	20562859
FLCN_HUMAN	FLCN	physical	20562859
AMOT_HUMAN	AMOT	physical	20562859
RBCC1_HUMAN	RB1CC1	physical	20562859
ULK1_HUMAN	ULK1	physical	20562859
GFPT1_HUMAN	GFPT1	physical	20562859
GDE_HUMAN	AGL	physical	20562859
SYPM_HUMAN	PARS2	physical	20562859
FNIP1_HUMAN	FNIP1	physical	20562859
DFFA_HUMAN	DFFA	physical	20562859
SMC1A_HUMAN	SMC1A	physical	20562859
ACACA_HUMAN	ACACA	physical	20562859
DNJB1_HUMAN	DNAJB1	physical	20562859
EPM2A_HUMAN	EPM2A	physical	18029386
AAKB2_HUMAN	PRKAB2	physical	19616115
NRAP_HUMAN	NRAP	physical	19616115
TMOD1_HUMAN	TMOD1	physical	19616115
UBC9_HUMAN	UBE2I	physical	19616115
PBIP1_HUMAN	PBXIP1	physical	19616115
SNW1_HUMAN	SNW1	physical	19616115
TRIP6_HUMAN	TRIP6	physical	19616115
MYOZ1_HUMAN	MYOZ1	physical	19616115
CS047_HUMAN	C19orf47	physical	19616115
RPTOR_HUMAN	RPTOR	physical	18439900
WWP1_HUMAN	WWP1	physical	23293026
AAKB2_HUMAN	PRKAB2	physical	25416956
AAKG1_HUMAN	PRKAG1	physical	25416956
VPS52_HUMAN	VPS52	physical	25416956
ITF2_HUMAN	TCF4	physical	25416956
TRIP6_HUMAN	TRIP6	physical	25416956
AIMP2_HUMAN	AIMP2	physical	25416956
ABI2_HUMAN	ABI2	physical	25416956
APBP2_HUMAN	APPBP2	physical	25416956
RBPMS_HUMAN	RBPMS	physical	25416956
NECA2_HUMAN	NECAB2	physical	25416956
HOMEZ_HUMAN	HOMEZ	physical	25416956
CIP1_HUMAN	CCNB1IP1	physical	25416956
HMBX1_HUMAN	HMBOX1	physical	25416956
T22D4_HUMAN	TSC22D4	physical	25416956
USBP1_HUMAN	USHBP1	physical	25416956
ZN397_HUMAN	ZNF397	physical	25416956
LMBL3_HUMAN	L3MBTL3	physical	25416956
RFX6_HUMAN	RFX6	physical	25416956
NUTM1_HUMAN	NUTM1	physical	25416956
KCTD1_HUMAN	KCTD1	physical	25416956
KIF24_HUMAN	KIF24	physical	25416956
KR103_HUMAN	KRTAP10-3	physical	25416956
NT2NL_HUMAN	NOTCH2NL	physical	25416956
ZBT8A_HUMAN	ZBTB8A	physical	25416956
BRCA1_HUMAN	BRCA1	physical	25184681
TRIP6_HUMAN	TRIP6	physical	16624523
PPM1F_HUMAN	PPM1F	physical	20801214
AAKG1_HUMAN	PRKAG1	physical	17012231
LMBL3_HUMAN	L3MBTL3	physical	21516116
AP2A_HUMAN	TFAP2A	physical	22561688
UBP10_HUMAN	USP10	physical	26876938
G3BP1_HUMAN	G3BP1	physical	25840010
DNMT1_HUMAN	DNMT1	physical	28143904
RBBP7_HUMAN	RBBP7	physical	28143904
HAT1_HUMAN	HAT1	physical	28143904

Drug and Disease Associations

Kegg Disease
There are no disease associations of PTM sites.
OMIM Disease
There are no disease associations of PTM sites.
Kegg Drug
There are no disease associations of PTM sites.
DrugBank
DB00945	Acetylsalicylic acid

Regulatory Network of AAPK2_HUMAN

Related Literatures of Post-Translational Modification

Acetylation
Reference	PubMed
"Lysine acetylation targets protein complexes and co-regulates majorcellular functions."; Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T.,Olsen J.V., Mann M.; Science 325:834-840(2009). Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-69, AND MASS SPECTROMETRY.	19608861 [Abstract]
Phosphorylation
Reference	PubMed
"Large-scale proteomics analysis of the human kinome."; Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G.,Mann M., Daub H.; Mol. Cell. Proteomics 8:1751-1764(2009). Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-377 AND SER-500, ANDMASS SPECTROMETRY.	19369195 [Abstract]
"Lys-N and trypsin cover complementary parts of the phosphoproteome ina refined SCX-based approach."; Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,Mohammed S.; Anal. Chem. 81:4493-4501(2009). Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-377, AND MASSSPECTROMETRY.	19413330 [Abstract]
"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-377, AND MASSSPECTROMETRY.	18669648 [Abstract]
"Kinase-selective enrichment enables quantitative phosphoproteomics ofthe kinome across the cell cycle."; Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R.,Greff Z., Keri G., Stemmann O., Mann M.; Mol. Cell 31:438-448(2008). Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-176 AND SER-377, ANDMASS SPECTROMETRY.	18691976 [Abstract]
"Combining protein-based IMAC, peptide-based IMAC, and MudPIT forefficient phosphoproteomic analysis."; Cantin G.T., Yi W., Lu B., Park S.K., Xu T., Lee J.-D.,Yates J.R. III; J. Proteome Res. 7:1346-1351(2008). Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-173 AND SER-176, ANDMASS SPECTROMETRY.	18220336 [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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