PRKAA2
entrez
5563
canonical
uniprot
P54646
canonical
ensembl
ENSG00000162409
resolver
ensp
ENSP00000360290
resolver
enst
ENST00000371244
resolver
genesymbol
PRKAA2
resolver
genesymbol_syn
AMPK
resolver
genesymbol_syn
AMPK2
resolver
hgnc
HGNC:9377
resolver
uniprot
Q9H1E8
resolver
uniprot
Q9UD43
resolver
uniprot_entry
AAPK2_HUMAN
resolver
uniprot_sec
Q9H1E8
resolver
uniprot_sec
Q9UD43
resolver
activity_regulation
ACTIVITY REGULATION: Activated by phosphorylation on Thr-172 by STK11/LKB1 (PubMed:15980064). Binding of AMP to non-catalytic gamma subunit (PRKAG1, PRKAG2 or PRKAG3) results in allosteric activation, inducing phosphorylation on Thr-172 (PubMed:15980064). AMP-binding to gamma subunit also sustains activity by preventing dephosphorylation of Thr-172 (PubMed:15980064). ADP also stimulates Thr-172 phosphorylation, without stimulating already phosphorylated AMPK (PubMed:15980064). ATP promotes dephosphorylation of Thr-172, rendering the enzyme inactive (PubMed:15980064). Under physiological conditions AMPK mainly exists in its inactive form in complex with ATP, which is much more abundant than AMP. AMPK is activated by antihyperglycemic drug metformin, a drug prescribed to patients with type 2 diabetes: in vivo, metformin seems to mainly inhibit liver gluconeogenesis. However, metformin can be used to activate AMPK in muscle and other cells in culture or ex vivo (PubMed:11602624). Activated by lithocholic acid in response to calorie restriction: activation is mediated by the AXIN1-STK11/LKB1 axis, which promotes phosphorylation by STK11/LKB1, leading to mTORC1 inhibition (By similarity). Selectively inhibited by compound C (6-[4-(2-Piperidin-1-yl-ethoxy)-phenyl)]-3-pyridin-4-yl-pyyrazolo[1,5-a] pyrimidine (PubMed:17307971, PubMed:17712357). Activated by resveratrol, a natural polyphenol present in red wine, and S17834, a synthetic polyphenol (PubMed:17307971, PubMed:17712357). Salicylate/aspirin directly activates kinase activity, primarily by inhibiting Thr-172 dephosphorylation. {ECO:0000250|UniProtKB:Q8BRK8, ECO:0000269|PubMed:11602624, ECO:0000269|PubMed:15980064, ECO:0000269|PubMed:21543851, ECO:0000269|PubMed:22517326, ECO:0000303|PubMed:17307971, ECO:0000303|PubMed:17712357}.
uniprot
proteins
amino_acid_sequence
MAEKQKHDGRVKIGHYVLGDTLGVGTFGKVKIGEHQLTGHKVAVKILNRQKIRSLDVVGKIKREIQNLKLFRHPHIIKLYQVISTPTDFFMVMEYVSGGELFDYICKHGRVEEMEARRLFQQILSAVDYCHRHMVVHRDLKPENVLLDAHMNAKIADFGLSNMMSDGEFLRTSCGSPNYAAPEVISGRLYAGPEVDIWSCGVILYALLCGTLPFDDEHVPTLFKKIRGGVFYIPEYLNRSVATLLMHMLQVDPLKRATIKDIREHEWFKQDLPSYLFPEDPSYDANVIDDEAVKEVCEKFECTESEVMNSLYSGDPQDQLAVAYHLIIDNRRIMNQASEFYLASSPPSGSFMDDSAMHIPPGLKPHPERMPPLIADSPKARCPLDALNTTKPKSLAVKKAKWHLGIRSQSKPYDIMAEVYRAMKQLDFEWKVVNAYHLRVRRKNPVTGNYVKMSLQLYLVDNRSYLLDFKSIDDEVVEQRSGSSTPQRSCSAAGLHRPRSSFDSTTAESHSLSGSLTGSLTGSTLSSVSPRLGSHTMDFFEMCASLITTLAR
uniprot
proteins
ec_number
2.7.11.1
uniprot
proteins
ec_number
2.7.11.31
uniprot
proteins
function
FUNCTION: Catalytic subunit of AMP-activated protein kinase (AMPK), an energy sensor protein kinase that plays a key role in regulating cellular energy metabolism (PubMed:17307971, PubMed:17712357). 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 (PubMed:17307971, PubMed:17712357). AMPK acts via direct phosphorylation of metabolic enzymes, and by longer-term effects via phosphorylation of transcription regulators (PubMed:17307971, PubMed:17712357). 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 (PubMed:7959015). Promotes lipolysis of lipid droplets by mediating phosphorylation of isoform 1 of CHKA (CHKalpha2) (PubMed:34077757). Regulates insulin-signaling and glycolysis by phosphorylating IRS1, PFKFB2 and PFKFB3 (By similarity). 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 (By similarity). 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 (PubMed:11518699, PubMed:11554766, PubMed:15866171, PubMed:17711846, PubMed:18184930). Acts as a key regulator of glucose homeostasis in liver by phosphorylating CRTC2/TORC2, leading to CRTC2/TORC2 sequestration in the cytoplasm (By similarity). In response to stress, phosphorylates 'Ser-36' of histone H2B (H2BS36ph), leading to promote transcription (By similarity). Acts as a key regulator of cell growth and proliferation by phosphorylating FNIP1, TSC2, RPTOR, WDR24 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 (PubMed:14651849, PubMed:20160076, PubMed:21205641). Also phosphorylates and inhibits GATOR2 subunit WDR24 in response to nutrient limitation, leading to suppress glucose-mediated mTORC1 activation (PubMed:36732624). In response to energetic stress, phosphorylates FNIP1, inactivating the non-canonical mTORC1 signaling, thereby promoting nuclear translocation of TFEB and TFE3, and inducing transcription of lysosomal or autophagy genes (PubMed:37079666). In response to nutrient limitation, promotes autophagy by phosphorylating and activating ATG1/ULK1 (PubMed:21205641). In that process, it also activates WDR45/WIPI4 (PubMed:28561066). Phosphorylates CASP6, thereby preventing its autoprocessing and subsequent activation (PubMed:32029622). AMPK also acts as a regulator of circadian rhythm by mediating phosphorylation of CRY1, leading to destabilize it (By similarity). May regulate the Wnt signaling pathway by phosphorylating CTNNB1, leading to stabilize it (By similarity). Also acts as a regulator of cellular polarity by remodeling the actin cytoskeleton; probably by indirectly activating myosin (PubMed:17486097). Also phosphorylates CFTR, EEF2K, KLC1, NOS3 and SLC12A1 (PubMed:12519745, PubMed:20074060). 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 (By similarity). Can inhibit the non-autophagy complex by phosphorylating PIK3C3 and can activate the pro-autophagy complex by phosphorylating BECN1 (By similarity). Upon glucose starvation, promotes ARF6 activation in a kinase-independent manner leading to cell migration (PubMed:36017701). Upon glucose deprivation mediates the phosphorylation of ACSS2 at 'Ser-659', which exposes the nuclear localization signal of ACSS2, required for its interaction with KPNA1 and nuclear translocation (PubMed:28552616). Upon stress, regulates mitochondrial fragmentation through phosphorylation of MTFR1L (PubMed:36367943). {ECO:0000250|UniProtKB:Q09137, ECO:0000250|UniProtKB:Q8BRK8, ECO:0000269|PubMed:11518699, ECO:0000269|PubMed:11554766, ECO:0000269|PubMed:12519745, ECO:0000269|PubMed:14651849, ECO:0000269|PubMed:15866171, ECO:0000269|PubMed:17486097, ECO:0000269|PubMed:17711846, ECO:0000269|PubMed:18184930, ECO:0000269|PubMed:20074060, ECO:0000269|PubMed:20160076, ECO:0000269|PubMed:21205641, ECO:0000269|PubMed:25687571, ECO:0000269|PubMed:28552616, ECO:0000269|PubMed:28561066, ECO:0000269|PubMed:32029622, ECO:0000269|PubMed:34077757, ECO:0000269|PubMed:36017701, ECO:0000269|PubMed:36367943, ECO:0000269|PubMed:36732624, ECO:0000269|PubMed:37079666, ECO:0000269|PubMed:7959015, ECO:0000303|PubMed:17307971, ECO:0000303|PubMed:17712357}.
uniprot
proteins
mass_dalton
62320
uniprot
proteins
mutagenesis
MUTAGEN 45; /note="K->R: Complete loss of kinase activity."; /evidence="ECO:0000305|PubMed:36017701"; MUTAGEN 172; /note="T->A: Loss of ARF6 activation. Loss of interaction with ACSS2."; /evidence="ECO:0000269|PubMed:28552616, ECO:0000269|PubMed:36017701"; MUTAGEN 172; /note="T->D: Phosphomimetic mutant."; /evidence="ECO:0000269|PubMed:21543851
uniprot
proteins
post_translational_modification
PTM: Ubiquitinated. {ECO:0000250|UniProtKB:Q8BRK8}.; PTM: Phosphorylated at Thr-172 by STK11/LKB1 in complex with STE20-related adapter-alpha (STRADA) pseudo kinase and CAB39. Also phosphorylated at Thr-172 by CAMKK2; triggered by a rise in intracellular calcium ions, without detectable changes in the AMP/ATP ratio. CAMKK1 can also phosphorylate Thr-172, but at much lower level. Dephosphorylated by protein phosphatase 2A and 2C (PP2A and PP2C). Phosphorylated by ULK1; leading to negatively regulate AMPK activity and suggesting the existence of a regulatory feedback loop between ULK1 and AMPK. Dephosphorylated by PPM1A and PPM1B at Thr-172 (mediated by STK11/LKB1). {ECO:0000269|PubMed:15980064, ECO:0000269|PubMed:21460634}.
uniprot
proteins
protein_family
CAMK Ser/Thr protein kinase family
uniprot
proteins
protein_family
Protein kinase superfamily
uniprot
proteins
protein_family
SNF1 subfamily
uniprot
proteins
pubmed
11518699
uniprot
proteins
pubmed
11554766
uniprot
proteins
pubmed
11602624
uniprot
proteins
pubmed
12519745
uniprot
proteins
pubmed
14651849
uniprot
proteins
pubmed
15489334
uniprot
proteins
pubmed
15866171
uniprot
proteins
pubmed
15980064
uniprot
proteins
pubmed
16710414
uniprot
proteins
pubmed
16959974
uniprot
proteins
pubmed
17307971
uniprot
proteins
pubmed
17344846
uniprot
proteins
pubmed
17486097
uniprot
proteins
pubmed
17711846
uniprot
proteins
pubmed
17712357
uniprot
proteins
pubmed
18184930
uniprot
proteins
pubmed
18669648
uniprot
proteins
pubmed
18691976
uniprot
proteins
pubmed
19369195
uniprot
proteins
pubmed
20074060
uniprot
proteins
pubmed
20124709
uniprot
proteins
pubmed
20160076
uniprot
proteins
pubmed
21205641
uniprot
proteins
pubmed
21269460
uniprot
proteins
pubmed
21460634
uniprot
proteins
pubmed
21543851
uniprot
proteins
pubmed
22517326
uniprot
proteins
pubmed
23088624
uniprot
proteins
pubmed
23186163
uniprot
proteins
pubmed
24767988
uniprot
proteins
pubmed
25687571
uniprot
proteins
pubmed
28552616
uniprot
proteins
pubmed
28561066
uniprot
proteins
pubmed
32029622
uniprot
proteins
pubmed
34077757
uniprot
proteins
pubmed
36017701
uniprot
proteins
pubmed
36367943
uniprot
proteins
pubmed
36732624
uniprot
proteins
pubmed
37079666
uniprot
proteins
pubmed
7959015
uniprot
proteins
pubmed
7988703
uniprot
proteins
sequence_length
552
uniprot
proteins
subcellular_location
SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:Q8BRK8}. Nucleus {ECO:0000269|PubMed:15866171}. Late endosome {ECO:0000250|UniProtKB:Q8BRK8}. Note=In response to stress, recruited by p53/TP53 to specific promoters (PubMed:15866171). Translocates to late endosomes in response to calorie restriction (By similarity). {ECO:0000250|UniProtKB:Q8BRK8, ECO:0000269|PubMed:15866171}.
uniprot
proteins