ID AAPK2_HUMAN Reviewed; 552 AA. AC P54646; Q9H1E8; Q9UD43; DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot. DT 16-APR-2002, sequence version 2. DT 27-MAR-2024, entry version 223. DE RecName: Full=5'-AMP-activated protein kinase catalytic subunit alpha-2; DE Short=AMPK subunit alpha-2; DE EC=2.7.11.1 {ECO:0000269|PubMed:28552616, ECO:0000269|PubMed:32029622, ECO:0000269|PubMed:36732624, ECO:0000269|PubMed:37079666}; DE AltName: Full=Acetyl-CoA carboxylase kinase; DE Short=ACACA kinase; DE AltName: Full=Hydroxymethylglutaryl-CoA reductase kinase; DE Short=HMGCR kinase; DE EC=2.7.11.31 {ECO:0000250|UniProtKB:Q09137}; GN Name=PRKAA2; Synonyms=AMPK, AMPK2; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA], AND FUNCTION. RC TISSUE=Heart; RX PubMed=7959015; DOI=10.1016/0378-1119(94)90174-0; RA Aguan K., Scott J., See C.G., Sarkar N.H.; RT "Characterization and chromosomal localization of the human homologue of a RT rat AMP-activated protein kinase-encoding gene: a major regulator of lipid RT metabolism in mammals."; RL Gene 149:345-350(1994). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA]. RC TISSUE=Skeletal muscle; RX PubMed=7988703; DOI=10.1016/0014-5793(94)01247-4; RA Beri R.K., Marley A.E., See C.G., Sopwith W.F., Aguan K., Carling D., RA Scott J., Carey F.; RT "Molecular cloning, expression and chromosomal localisation of human AMP- RT activated protein kinase."; RL FEBS Lett. 356:117-121(1994). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=16710414; DOI=10.1038/nature04727; RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A., RA Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C., RA Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K., RA Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C., RA Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W., RA Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J., RA Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., RA Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., RA Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., RA Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H., RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L., RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J., RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S., RA Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K., RA Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R., RA Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M., RA Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S., RA Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J., RA Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., RA McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N., RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V., RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J., RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E., RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S., RA Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M., RA White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H., RA Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E., RA Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G., RA Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R.; RT "The DNA sequence and biological annotation of human chromosome 1."; RL Nature 441:315-321(2006). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [5] RP FUNCTION. RX PubMed=11554766; DOI=10.1006/bbrc.2001.5627; RA Imamura K., Ogura T., Kishimoto A., Kaminishi M., Esumi H.; RT "Cell cycle regulation via p53 phosphorylation by a 5'-AMP activated RT protein kinase activator, 5-aminoimidazole-4-carboxamide-1-beta-D- RT ribofuranoside, in a human hepatocellular carcinoma cell line."; RL Biochem. Biophys. Res. Commun. 287:562-567(2001). RN [6] RP FUNCTION IN PHOSPHORYLATION OF EP300. RX PubMed=11518699; DOI=10.1074/jbc.c100316200; RA Yang W., Hong Y.H., Shen X.Q., Frankowski C., Camp H.S., Leff T.; RT "Regulation of transcription by AMP-activated protein kinase: RT phosphorylation of p300 blocks its interaction with nuclear receptors."; RL J. Biol. Chem. 276:38341-38344(2001). RN [7] RP ACTIVITY REGULATION. RX PubMed=11602624; DOI=10.1172/jci13505; RA Zhou G., Myers R., Li Y., Chen Y., Shen X., Fenyk-Melody J., Wu M., RA Ventre J., Doebber T., Fujii N., Musi N., Hirshman M.F., Goodyear L.J., RA Moller D.E.; RT "Role of AMP-activated protein kinase in mechanism of metformin action."; RL J. Clin. Invest. 108:1167-1174(2001). RN [8] RP FUNCTION IN PHOSPHORYLATION OF CFTR. RX PubMed=12519745; DOI=10.1152/ajpcell.00227.2002; RA Hallows K.R., Kobinger G.P., Wilson J.M., Witters L.A., Foskett J.K.; RT "Physiological modulation of CFTR activity by AMP-activated protein kinase RT in polarized T84 cells."; RL Am. J. Physiol. 284:C1297-C1308(2003). RN [9] RP FUNCTION IN PHOSPHORYLATION OF TSC2. RX PubMed=14651849; DOI=10.1016/s0092-8674(03)00929-2; RA Inoki K., Zhu T., Guan K.L.; RT "TSC2 mediates cellular energy response to control cell growth and RT survival."; RL Cell 115:577-590(2003). RN [10] RP PHOSPHORYLATION AT THR-172, AND ACTIVITY REGULATION. RX PubMed=15980064; DOI=10.1074/jbc.m503824200; RA Hurley R.L., Anderson K.A., Franzone J.M., Kemp B.E., Means A.R., RA Witters L.A.; RT "The Ca2+/calmodulin-dependent protein kinase kinases are AMP-activated RT protein kinase kinases."; RL J. Biol. Chem. 280:29060-29066(2005). RN [11] RP FUNCTION, AND SUBCELLULAR LOCATION. RX PubMed=15866171; DOI=10.1016/j.molcel.2005.03.027; RA Jones R.G., Plas D.R., Kubek S., Buzzai M., Mu J., Xu Y., Birnbaum M.J., RA Thompson C.B.; RT "AMP-activated protein kinase induces a p53-dependent metabolic RT checkpoint."; RL Mol. Cell 18:283-293(2005). RN [12] RP FUNCTION IN PHOSPHORYLATION OF FOXO3. RX PubMed=17711846; DOI=10.1074/jbc.m705325200; RA Greer E.L., Oskoui P.R., Banko M.R., Maniar J.M., Gygi M.P., Gygi S.P., RA Brunet A.; RT "The energy sensor AMP-activated protein kinase directly regulates the RT mammalian FOXO3 transcription factor."; RL J. Biol. Chem. 282:30107-30119(2007). RN [13] RP FUNCTION IN CELL POLARITY. RX PubMed=17486097; DOI=10.1038/nature05828; RA Lee J.H., Koh H., Kim M., Kim Y., Lee S.Y., Karess R.E., Lee S.H., RA Shong M., Kim J.M., Kim J., Chung J.; RT "Energy-dependent regulation of cell structure by AMP-activated protein RT kinase."; RL Nature 447:1017-1020(2007). RN [14] RP FUNCTION IN PHOSPHORYLATION OF HDAC5. RX PubMed=18184930; DOI=10.2337/db07-0843; RA McGee S.L., van Denderen B.J., Howlett K.F., Mollica J., Schertzer J.D., RA Kemp B.E., Hargreaves M.; RT "AMP-activated protein kinase regulates GLUT4 transcription by RT phosphorylating histone deacetylase 5."; RL Diabetes 57:860-867(2008). RN [15] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-377, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007; RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R., RA Greff Z., Keri G., Stemmann O., Mann M.; RT "Kinase-selective enrichment enables quantitative phosphoproteomics of the RT kinome across the cell cycle."; RL Mol. Cell 31:438-448(2008). RN [16] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=18669648; DOI=10.1073/pnas.0805139105; RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., RA Elledge S.J., Gygi S.P.; RT "A quantitative atlas of mitotic phosphorylation."; RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008). RN [17] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-377, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=19369195; DOI=10.1074/mcp.m800588-mcp200; RA Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G., RA Mann M., Daub H.; RT "Large-scale proteomics analysis of the human kinome."; RL Mol. Cell. Proteomics 8:1751-1764(2009). RN [18] RP FUNCTION IN PHOSPHORYLATION OF KLC1. RX PubMed=20074060; DOI=10.1042/bst0380205; RA McDonald A., Fogarty S., Leclerc I., Hill E.V., Hardie D.G., Rutter G.A.; RT "Cell-wide analysis of secretory granule dynamics in three dimensions in RT living pancreatic beta-cells: evidence against a role for AMPK-dependent RT phosphorylation of KLC1 at Ser517/Ser520 in glucose-stimulated insulin RT granule movement."; RL Biochem. Soc. Trans. 38:205-208(2010). RN [19] RP FUNCTION. RX PubMed=20160076; DOI=10.1073/pnas.0913860107; RA Alexander A., Cai S.L., Kim J., Nanez A., Sahin M., MacLean K.H., Inoki K., RA Guan K.L., Shen J., Person M.D., Kusewitt D., Mills G.B., Kastan M.B., RA Walker C.L.; RT "ATM signals to TSC2 in the cytoplasm to regulate mTORC1 in response to RT ROS."; RL Proc. Natl. Acad. Sci. U.S.A. 107:4153-4158(2010). RN [20] RP PHOSPHORYLATION BY ULK1. RX PubMed=21460634; DOI=10.4161/auto.7.7.15451; RA Loffler A.S., Alers S., Dieterle A.M., Keppeler H., Franz-Wachtel M., RA Kundu M., Campbell D.G., Wesselborg S., Alessi D.R., Stork B.; RT "Ulk1-mediated phosphorylation of AMPK constitutes a negative regulatory RT feedback loop."; RL Autophagy 7:696-706(2011). RN [21] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21269460; DOI=10.1186/1752-0509-5-17; RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., RA Bennett K.L., Superti-Furga G., Colinge J.; RT "Initial characterization of the human central proteome."; RL BMC Syst. Biol. 5:17-17(2011). RN [22] RP FUNCTION IN PHOSPHORYLATION OF ULK1. RX PubMed=21205641; DOI=10.1126/science.1196371; RA Egan D.F., Shackelford D.B., Mihaylova M.M., Gelino S., Kohnz R.A., RA Mair W., Vasquez D.S., Joshi A., Gwinn D.M., Taylor R., Asara J.M., RA Fitzpatrick J., Dillin A., Viollet B., Kundu M., Hansen M., Shaw R.J.; RT "Phosphorylation of ULK1 (hATG1) by AMP-activated protein kinase connects RT energy sensing to mitophagy."; RL Science 331:456-461(2011). RN [23] RP REVIEW ON FUNCTION. RX PubMed=17307971; DOI=10.1161/01.res.0000256090.42690.05; RA Towler M.C., Hardie D.G.; RT "AMP-activated protein kinase in metabolic control and insulin signaling."; RL Circ. Res. 100:328-341(2007). RN [24] RP REVIEW ON FUNCTION. RX PubMed=17712357; DOI=10.1038/nrm2249; RA Hardie D.G.; RT "AMP-activated/SNF1 protein kinases: conserved guardians of cellular RT energy."; RL Nat. Rev. Mol. Cell Biol. 8:774-785(2007). RN [25] RP ACTIVITY REGULATION BY SALICYLATE. RX PubMed=22517326; DOI=10.1126/science.1215327; RA Hawley S.A., Fullerton M.D., Ross F.A., Schertzer J.D., Chevtzoff C., RA Walker K.J., Peggie M.W., Zibrova D., Green K.A., Mustard K.J., Kemp B.E., RA Sakamoto K., Steinberg G.R., Hardie D.G.; RT "The ancient drug salicylate directly activates AMP-activated protein RT kinase."; RL Science 336:918-922(2012). RN [26] RP DEPHOSPHORYLATION AT THR-172. RX PubMed=23088624; DOI=10.1042/bj20121201; RA Chida T., Ando M., Matsuki T., Masu Y., Nagaura Y., Takano-Yamamoto T., RA Tamura S., Kobayashi T.; RT "N-Myristoylation is essential for protein phosphatases PPM1A and PPM1B to RT dephosphorylate their physiological substrates in cells."; RL Biochem. J. 449:741-749(2013). RN [27] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-377, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=23186163; DOI=10.1021/pr300630k; RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J., RA Mohammed S.; RT "Toward a comprehensive characterization of a human cancer cell RT phosphoproteome."; RL J. Proteome Res. 12:260-271(2013). RN [28] RP PHOSPHORYLATION AT THR-172. RX PubMed=24767988; DOI=10.1016/j.celrep.2014.03.065; RA Lanning N.J., Looyenga B.D., Kauffman A.L., Niemi N.M., Sudderth J., RA DeBerardinis R.J., MacKeigan J.P.; RT "A mitochondrial RNAi screen defines cellular bioenergetic determinants and RT identifies an adenylate kinase as a key regulator of ATP levels."; RL Cell Rep. 7:907-917(2014). RN [29] RP FUNCTION, AND SUBUNIT. RX PubMed=25687571; DOI=10.1074/mcp.m114.047159; RA Boutchueng-Djidjou M., Collard-Simard G., Fortier S., Hebert S.S., RA Kelly I., Landry C.R., Faure R.L.; RT "The last enzyme of the de novo purine synthesis pathway 5-aminoimidazole- RT 4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase (ATIC) RT plays a central role in insulin signaling and the Golgi/endosomes protein RT network."; RL Mol. Cell. Proteomics 14:1079-1092(2015). RN [30] RP FUNCTION, CATALYTIC ACTIVITY, PHOSPHORYLATION AT THR-172, INTERACTION WITH RP ACSS2, AND MUTAGENESIS OF THR-172. RX PubMed=28552616; DOI=10.1016/j.molcel.2017.04.026; RA Li X., Yu W., Qian X., Xia Y., Zheng Y., Lee J.H., Li W., Lyu J., Rao G., RA Zhang X., Qian C.N., Rozen S.G., Jiang T., Lu Z.; RT "Nucleus-Translocated ACSS2 Promotes Gene Transcription for Lysosomal RT Biogenesis and Autophagy."; RL Mol. Cell 66:684-697(2017). RN [31] RP FUNCTION. RX PubMed=28561066; DOI=10.1038/ncomms15637; RA Bakula D., Mueller A.J., Zuleger T., Takacs Z., Franz-Wachtel M., RA Thost A.K., Brigger D., Tschan M.P., Frickey T., Robenek H., Macek B., RA Proikas-Cezanne T.; RT "WIPI3 and WIPI4 beta-propellers are scaffolds for LKB1-AMPK-TSC signalling RT circuits in the control of autophagy."; RL Nat. Commun. 8:15637-15637(2017). RN [32] RP FUNCTION, AND CATALYTIC ACTIVITY. RX PubMed=32029622; DOI=10.1126/science.aay0542; RA Zhao P., Sun X., Chaggan C., Liao Z., In Wong K., He F., Singh S., RA Loomba R., Karin M., Witztum J.L., Saltiel A.R.; RT "An AMPK-caspase-6 axis controls liver damage in nonalcoholic RT steatohepatitis."; RL Science 367:652-660(2020). RN [33] RP FUNCTION. RX PubMed=34077757; DOI=10.1016/j.molcel.2021.05.005; RA Liu R., Lee J.H., Li J., Yu R., Tan L., Xia Y., Zheng Y., Bian X.L., RA Lorenzi P.L., Chen Q., Lu Z.; RT "Choline kinase alpha 2 acts as a protein kinase to promote lipolysis of RT lipid droplets."; RL Mol. Cell 81:2722-2735(2021). RN [34] RP FUNCTION, AND CATALYTIC ACTIVITY. RX PubMed=36732624; DOI=10.1038/s42255-022-00732-4; RA Dai X., Jiang C., Jiang Q., Fang L., Yu H., Guo J., Yan P., Chi F., RA Zhang T., Inuzuka H., Asara J.M., Wang P., Guo J., Wei W.; RT "AMPK-dependent phosphorylation of the GATOR2 component WDR24 suppresses RT glucose-mediated mTORC1 activation."; RL Nat. Metab. 5:265-276(2023). RN [35] RP FUNCTION, AND CATALYTIC ACTIVITY. RX PubMed=37079666; DOI=10.1126/science.abj5559; RA Malik N., Ferreira B.I., Hollstein P.E., Curtis S.D., Trefts E., RA Weiser Novak S., Yu J., Gilson R., Hellberg K., Fang L., Sheridan A., RA Hah N., Shadel G.S., Manor U., Shaw R.J.; RT "Induction of lysosomal and mitochondrial biogenesis by AMPK RT phosphorylation of FNIP1."; RL Science 380:eabj5559-eabj5559(2023). RN [36] RP FUNCTION, INTERACTION WITH ARF6, AND MUTAGENESIS OF LYS-45 AND THR-172. RX PubMed=36017701; DOI=10.1242/jcs.259609; RA Chen K.J., Hsu J.W., Lee F.S.; RT "AMPK promotes Arf6 activation in a kinase-independent manner upon glucose RT starvation."; RL J. Cell Sci. 135:0-0(2022). RN [37] RP X-RAY CRYSTALLOGRAPHY (1.85 ANGSTROMS) OF 6-279. RX PubMed=20124709; DOI=10.1107/s1744309109052543; RA Littler D.R., Walker J.R., Davis T., Wybenga-Groot L.E., Finerty P.J. Jr., RA Newman E., Mackenzie F., Dhe-Paganon S.; RT "A conserved mechanism of autoinhibition for the AMPK kinase domain: ATP- RT binding site and catalytic loop refolding as a means of regulation."; RL Acta Crystallogr. F 66:143-151(2010). RN [38] RP X-RAY CRYSTALLOGRAPHY (2.08 ANGSTROMS) OF 6-279 OF MUTANT THR-172 IN RP COMPLEX WITH COMPOUND C, ACTIVITY REGULATION, AND MUTAGENESIS OF THR-172. RX PubMed=21543851; DOI=10.1107/s0907444911010201; RA Handa N., Takagi T., Saijo S., Kishishita S., Takaya D., Toyama M., RA Terada T., Shirouzu M., Suzuki A., Lee S., Yamauchi T., Okada-Iwabu M., RA Iwabu M., Kadowaki T., Minokoshi Y., Yokoyama S.; RT "Structural basis for compound C inhibition of the human AMP-activated RT protein kinase alpha2 subunit kinase domain."; RL Acta Crystallogr. D 67:480-487(2011). RN [39] RP VARIANTS [LARGE SCALE ANALYSIS] THR-371 AND GLY-523. RX PubMed=16959974; DOI=10.1126/science.1133427; RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D., RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S., Buckhaults P., RA Farrell C., Meeh P., Markowitz S.D., Willis J., Dawson D., Willson J.K.V., RA Gazdar A.F., Hartigan J., Wu L., Liu C., Parmigiani G., Park B.H., RA Bachman K.E., Papadopoulos N., Vogelstein B., Kinzler K.W., RA Velculescu V.E.; RT "The consensus coding sequences of human breast and colorectal cancers."; RL Science 314:268-274(2006). RN [40] RP VARIANTS [LARGE SCALE ANALYSIS] THR-371 AND GLN-407. RX PubMed=17344846; DOI=10.1038/nature05610; RA Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G., RA Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S., RA Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G., RA Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K., RA Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D., RA Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R., RA Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A., RA Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F., RA Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F., RA Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G., RA Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R., RA Futreal P.A., Stratton M.R.; RT "Patterns of somatic mutation in human cancer genomes."; RL Nature 446:153-158(2007). CC -!- FUNCTION: Catalytic subunit of AMP-activated protein kinase (AMPK), an CC energy sensor protein kinase that plays a key role in regulating CC cellular energy metabolism (PubMed:17307971, PubMed:17712357). In CC response to reduction of intracellular ATP levels, AMPK activates CC energy-producing pathways and inhibits energy-consuming processes: CC inhibits protein, carbohydrate and lipid biosynthesis, as well as cell CC growth and proliferation (PubMed:17307971, PubMed:17712357). AMPK acts CC via direct phosphorylation of metabolic enzymes, and by longer-term CC effects via phosphorylation of transcription regulators CC (PubMed:17307971, PubMed:17712357). Regulates lipid synthesis by CC phosphorylating and inactivating lipid metabolic enzymes such as ACACA, CC ACACB, GYS1, HMGCR and LIPE; regulates fatty acid and cholesterol CC synthesis by phosphorylating acetyl-CoA carboxylase (ACACA and ACACB) CC and hormone-sensitive lipase (LIPE) enzymes, respectively CC (PubMed:7959015). Promotes lipolysis of lipid droplets by mediating CC phosphorylation of isoform 1 of CHKA (CHKalpha2) (PubMed:34077757). CC Regulates insulin-signaling and glycolysis by phosphorylating IRS1, CC PFKFB2 and PFKFB3 (By similarity). Involved in insulin receptor/INSR CC internalization (PubMed:25687571). AMPK stimulates glucose uptake in CC muscle by increasing the translocation of the glucose transporter CC SLC2A4/GLUT4 to the plasma membrane, possibly by mediating CC phosphorylation of TBC1D4/AS160 (By similarity). Regulates CC transcription and chromatin structure by phosphorylating transcription CC regulators involved in energy metabolism such as CRTC2/TORC2, FOXO3, CC histone H2B, HDAC5, MEF2C, MLXIPL/ChREBP, EP300, HNF4A, p53/TP53, CC SREBF1, SREBF2 and PPARGC1A (PubMed:11554766, PubMed:11518699, CC PubMed:15866171, PubMed:17711846, PubMed:18184930). Acts as a key CC regulator of glucose homeostasis in liver by phosphorylating CC CRTC2/TORC2, leading to CRTC2/TORC2 sequestration in the cytoplasm (By CC similarity). In response to stress, phosphorylates 'Ser-36' of histone CC H2B (H2BS36ph), leading to promote transcription (By similarity). Acts CC as a key regulator of cell growth and proliferation by phosphorylating CC FNIP1, TSC2, RPTOR, WDR24 and ATG1/ULK1: in response to nutrient CC limitation, negatively regulates the mTORC1 complex by phosphorylating CC RPTOR component of the mTORC1 complex and by phosphorylating and CC activating TSC2 (PubMed:14651849, PubMed:20160076, PubMed:21205641). CC Also phosphorylates and inhibits GATOR2 subunit WDR24 in response to CC nutrient limitation, leading to suppress glucose-mediated mTORC1 CC activation (PubMed:36732624). In response to energetic stress, CC phosphorylates FNIP1, inactivating the non-canonical mTORC1 signaling, CC thereby promoting nuclear translocation of TFEB and TFE3, and inducing CC transcription of lysosomal or autophagy genes (PubMed:37079666). In CC response to nutrient limitation, promotes autophagy by phosphorylating CC and activating ATG1/ULK1 (PubMed:21205641). In that process also CC activates WDR45/WIPI4 (PubMed:28561066). Phosphorylates CASP6, thereby CC preventing its autoprocessing and subsequent activation CC (PubMed:32029622). AMPK also acts as a regulator of circadian rhythm by CC mediating phosphorylation of CRY1, leading to destabilize it (By CC similarity). May regulate the Wnt signaling pathway by phosphorylating CC CTNNB1, leading to stabilize it (By similarity). Also acts as a CC regulator of cellular polarity by remodeling the actin cytoskeleton; CC probably by indirectly activating myosin (PubMed:17486097). Also CC phosphorylates CFTR, EEF2K, KLC1, NOS3 and SLC12A1 (PubMed:12519745, CC PubMed:20074060). Plays an important role in the differential CC regulation of pro-autophagy (composed of PIK3C3, BECN1, PIK3R4 and CC UVRAG or ATG14) and non-autophagy (composed of PIK3C3, BECN1 and CC PIK3R4) complexes, in response to glucose starvation (By similarity). CC Can inhibit the non-autophagy complex by phosphorylating PIK3C3 and can CC activate the pro-autophagy complex by phosphorylating BECN1 (By CC similarity). Upon glucose starvation, promotes ARF6 activation in a CC kinase-independent manner leading to cell migration (PubMed:36017701). CC Upon glucose deprivation mediates the phosphorylation of ACSS2 at 'Ser- CC 659', which exposes the nuclear localization signal of ACSS2, required CC for its interaction with KPNA1 and nuclear translocation CC (PubMed:28552616). {ECO:0000250|UniProtKB:Q09137, CC ECO:0000250|UniProtKB:Q8BRK8, ECO:0000269|PubMed:11518699, CC ECO:0000269|PubMed:11554766, ECO:0000269|PubMed:12519745, CC ECO:0000269|PubMed:14651849, ECO:0000269|PubMed:15866171, CC ECO:0000269|PubMed:17486097, ECO:0000269|PubMed:17711846, CC ECO:0000269|PubMed:18184930, ECO:0000269|PubMed:20074060, CC ECO:0000269|PubMed:20160076, ECO:0000269|PubMed:21205641, CC ECO:0000269|PubMed:25687571, ECO:0000269|PubMed:28552616, CC ECO:0000269|PubMed:28561066, ECO:0000269|PubMed:32029622, CC ECO:0000269|PubMed:34077757, ECO:0000269|PubMed:36017701, CC ECO:0000269|PubMed:36732624, ECO:0000269|PubMed:37079666, CC ECO:0000269|PubMed:7959015, ECO:0000303|PubMed:17307971, CC ECO:0000303|PubMed:17712357}. CC -!- CATALYTIC ACTIVITY: CC Reaction=ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl- CC [protein]; Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA- CC COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616, CC ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.1; CC Evidence={ECO:0000269|PubMed:28552616, ECO:0000269|PubMed:32029622, CC ECO:0000269|PubMed:36732624, ECO:0000269|PubMed:37079666}; CC -!- CATALYTIC ACTIVITY: CC Reaction=ATP + L-threonyl-[protein] = ADP + H(+) + O-phospho-L- CC threonyl-[protein]; Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060, CC Rhea:RHEA-COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013, CC ChEBI:CHEBI:30616, ChEBI:CHEBI:61977, ChEBI:CHEBI:456216; CC EC=2.7.11.1; Evidence={ECO:0000250|UniProtKB:Q09137}; CC -!- CATALYTIC ACTIVITY: CC Reaction=ATP + L-seryl-[acetyl-CoA carboxylase] = ADP + H(+) + O- CC phospho-L-seryl-[acetyl-CoA carboxylase]; Xref=Rhea:RHEA:20333, CC Rhea:RHEA-COMP:13722, Rhea:RHEA-COMP:13723, ChEBI:CHEBI:15378, CC ChEBI:CHEBI:29999, ChEBI:CHEBI:30616, ChEBI:CHEBI:83421, CC ChEBI:CHEBI:456216; Evidence={ECO:0000250|UniProtKB:Q09137}; CC -!- CATALYTIC ACTIVITY: CC Reaction=ATP + L-seryl-[3-hydroxy-3-methylglutaryl-coenzyme A CC reductase] = ADP + H(+) + O-phospho-L-seryl-[3-hydroxy-3- CC methylglutaryl-coenzyme A reductase]; Xref=Rhea:RHEA:23172, CC Rhea:RHEA-COMP:13692, Rhea:RHEA-COMP:13693, ChEBI:CHEBI:15378, CC ChEBI:CHEBI:29999, ChEBI:CHEBI:30616, ChEBI:CHEBI:83421, CC ChEBI:CHEBI:456216; EC=2.7.11.31; CC Evidence={ECO:0000250|UniProtKB:Q09137}; CC -!- COFACTOR: CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420; Evidence={ECO:0000305}; CC -!- ACTIVITY REGULATION: Activated by phosphorylation on Thr-172 CC (PubMed:15980064). Binding of AMP to non-catalytic gamma subunit CC (PRKAG1, PRKAG2 or PRKAG3) results in allosteric activation, inducing CC phosphorylation on Thr-172 (PubMed:15980064). AMP-binding to gamma CC subunit also sustains activity by preventing dephosphorylation of Thr- CC 172 (PubMed:15980064). ADP also stimulates Thr-172 phosphorylation, CC without stimulating already phosphorylated AMPK (PubMed:15980064). ATP CC promotes dephosphorylation of Thr-172, rendering the enzyme inactive CC (PubMed:15980064). Under physiological conditions AMPK mainly exists in CC its inactive form in complex with ATP, which is much more abundant than CC AMP. AMPK is activated by antihyperglycemic drug metformin, a drug CC prescribed to patients with type 2 diabetes: in vivo, metformin seems CC to mainly inhibit liver gluconeogenesis. However, metformin can be used CC to activate AMPK in muscle and other cells in culture or ex vivo CC (PubMed:11602624). Selectively inhibited by compound C (6-[4-(2- CC Piperidin-1-yl-ethoxy)-phenyl)]-3-pyridin-4-yl-pyyrazolo[1,5-a] CC pyrimidine. Activated by resveratrol, a natural polyphenol present in CC red wine, and S17834, a synthetic polyphenol. Salicylate/aspirin CC directly activates kinase activity, primarily by inhibiting Thr-172 CC dephosphorylation. {ECO:0000269|PubMed:11602624, CC ECO:0000269|PubMed:15980064, ECO:0000269|PubMed:21543851, CC ECO:0000269|PubMed:22517326}. CC -!- SUBUNIT: AMPK is a heterotrimer of an alpha catalytic subunit (PRKAA1 CC or PRKAA2), a beta (PRKAB1 or PRKAB2) and a gamma non-catalytic CC subunits (PRKAG1, PRKAG2 or PRKAG3) (PubMed:21543851). Interacts with CC FNIP1 and FNIP2. Associates with internalized insulin receptor/INSR CC complexes on Golgi/endosomal membranes; PRKAA2/AMPK2 together with ATIC CC and HACD3/PTPLAD1 is proposed to be part of a signaling network CC regulating INSR autophosphorylation and endocytosis (PubMed:25687571). CC Interacts with ARF6 (PubMed:36017701). The phosphorylated form at Thr- CC 172 mediated by CamKK2 interacts with ACSS2 (PubMed:28552616). CC {ECO:0000269|PubMed:21543851, ECO:0000269|PubMed:25687571, CC ECO:0000269|PubMed:28552616, ECO:0000269|PubMed:36017701}. CC -!- INTERACTION: CC P54646; Q8IZP0-5: ABI1; NbExp=3; IntAct=EBI-1383852, EBI-11743294; CC P54646; Q9NYB9: ABI2; NbExp=5; IntAct=EBI-1383852, EBI-743598; CC P54646; Q9NYB9-2: ABI2; NbExp=3; IntAct=EBI-1383852, EBI-11096309; CC P54646; Q13155: AIMP2; NbExp=3; IntAct=EBI-1383852, EBI-745226; CC P54646; Q9ULX6: AKAP8L; NbExp=3; IntAct=EBI-1383852, EBI-357530; CC P54646; A2BDD9: AMOT; NbExp=3; IntAct=EBI-1383852, EBI-17286414; CC P54646; Q9Y2J4: AMOTL2; NbExp=3; IntAct=EBI-1383852, EBI-746752; CC P54646; Q9NYG5-2: ANAPC11; NbExp=3; IntAct=EBI-1383852, EBI-12224467; CC P54646; Q92624: APPBP2; NbExp=3; IntAct=EBI-1383852, EBI-743771; CC P54646; Q96B67: ARRDC3; NbExp=3; IntAct=EBI-1383852, EBI-2875665; CC P54646; Q5T686: AVPI1; NbExp=3; IntAct=EBI-1383852, EBI-8640233; CC P54646; Q9P1Z2: CALCOCO1; NbExp=3; IntAct=EBI-1383852, EBI-749920; CC P54646; Q13137: CALCOCO2; NbExp=3; IntAct=EBI-1383852, EBI-739580; CC P54646; P0C7W6: CCDC172; NbExp=3; IntAct=EBI-1383852, EBI-2548868; CC P54646; Q9NPC3: CCNB1IP1; NbExp=4; IntAct=EBI-1383852, EBI-745269; CC P54646; Q00587-2: CDC42EP1; NbExp=3; IntAct=EBI-1383852, EBI-11027409; CC P54646; Q01850: CDR2; NbExp=3; IntAct=EBI-1383852, EBI-1181367; CC P54646; O14627: CDX4; NbExp=3; IntAct=EBI-1383852, EBI-10181162; CC P54646; Q8N684-3: CPSF7; NbExp=3; IntAct=EBI-1383852, EBI-11523759; CC P54646; O75638-2: CTAG2; NbExp=3; IntAct=EBI-1383852, EBI-12265122; CC P54646; A8MQ03: CYSRT1; NbExp=3; IntAct=EBI-1383852, EBI-3867333; CC P54646; Q9NQM4: DNAAF6; NbExp=3; IntAct=EBI-1383852, EBI-10239299; CC P54646; P50570: DNM2; NbExp=3; IntAct=EBI-1383852, EBI-346547; CC P54646; Q92997: DVL3; NbExp=3; IntAct=EBI-1383852, EBI-739789; CC P54646; Q9Y6C2-2: EMILIN1; NbExp=3; IntAct=EBI-1383852, EBI-11748557; CC P54646; O95208-2: EPN2; NbExp=3; IntAct=EBI-1383852, EBI-12135243; CC P54646; Q53EP0-3: FNDC3B; NbExp=3; IntAct=EBI-1383852, EBI-10242151; CC P54646; Q6FG41: FOS; NbExp=3; IntAct=EBI-1383852, EBI-10198738; CC P54646; O75420: GIGYF1; NbExp=3; IntAct=EBI-1383852, EBI-947774; CC P54646; P08151: GLI1; NbExp=3; IntAct=EBI-1383852, EBI-308084; CC P54646; Q08379: GOLGA2; NbExp=3; IntAct=EBI-1383852, EBI-618309; CC P54646; Q9NYA3: GOLGA6A; NbExp=3; IntAct=EBI-1383852, EBI-11163335; CC P54646; O75791: GRAP2; NbExp=3; IntAct=EBI-1383852, EBI-740418; CC P54646; P28799: GRN; NbExp=3; IntAct=EBI-1383852, EBI-747754; CC P54646; Q6NT76: HMBOX1; NbExp=3; IntAct=EBI-1383852, EBI-2549423; CC P54646; Q8IX15-3: HOMEZ; NbExp=3; IntAct=EBI-1383852, EBI-10172004; CC P54646; Q13422-7: IKZF1; NbExp=3; IntAct=EBI-1383852, EBI-11522367; CC P54646; Q9UKT9: IKZF3; NbExp=3; IntAct=EBI-1383852, EBI-747204; CC P54646; Q719H9: KCTD1; NbExp=3; IntAct=EBI-1383852, EBI-9027502; CC P54646; Q7L273: KCTD9; NbExp=3; IntAct=EBI-1383852, EBI-4397613; CC P54646; Q86T90: KIAA1328; NbExp=3; IntAct=EBI-1383852, EBI-3437878; CC P54646; Q96L93-6: KIF16B; NbExp=3; IntAct=EBI-1383852, EBI-10988217; CC P54646; Q5T7B8-2: KIF24; NbExp=3; IntAct=EBI-1383852, EBI-10213781; CC P54646; Q9BVG8: KIFC3; NbExp=4; IntAct=EBI-1383852, EBI-2125614; CC P54646; P08779: KRT16; NbExp=3; IntAct=EBI-1383852, EBI-356410; CC P54646; Q15323: KRT31; NbExp=3; IntAct=EBI-1383852, EBI-948001; CC P54646; Q8IUG1: KRTAP1-3; NbExp=3; IntAct=EBI-1383852, EBI-11749135; CC P54646; P60411: KRTAP10-9; NbExp=3; IntAct=EBI-1383852, EBI-10172052; CC P54646; Q96JM7: L3MBTL3; NbExp=3; IntAct=EBI-1383852, EBI-2686809; CC P54646; Q96JM7-2: L3MBTL3; NbExp=3; IntAct=EBI-1383852, EBI-11985629; CC P54646; P80188: LCN2; NbExp=3; IntAct=EBI-1383852, EBI-11911016; CC P54646; Q9BRK4: LZTS2; NbExp=3; IntAct=EBI-1383852, EBI-741037; CC P54646; Q13064: MKRN3; NbExp=3; IntAct=EBI-1383852, EBI-2340269; CC P54646; Q6PF18: MORN3; NbExp=3; IntAct=EBI-1383852, EBI-9675802; CC P54646; Q9Y605: MRFAP1; NbExp=3; IntAct=EBI-1383852, EBI-995714; CC P54646; Q5JR59-3: MTUS2; NbExp=4; IntAct=EBI-1383852, EBI-11522433; CC P54646; P12524-2: MYCL; NbExp=3; IntAct=EBI-1383852, EBI-18936665; CC P54646; Q15742: NAB2; NbExp=3; IntAct=EBI-1383852, EBI-8641936; CC P54646; Q7Z6G3-2: NECAB2; NbExp=3; IntAct=EBI-1383852, EBI-10172876; CC P54646; Q15233-2: NONO; NbExp=3; IntAct=EBI-1383852, EBI-10203843; CC P54646; Q7Z3S9: NOTCH2NLA; NbExp=3; IntAct=EBI-1383852, EBI-945833; CC P54646; Q96F24: NRBF2; NbExp=3; IntAct=EBI-1383852, EBI-2362014; CC P54646; Q86Y26: NUTM1; NbExp=3; IntAct=EBI-1383852, EBI-10178410; CC P54646; Q494U1-3: PLEKHN1; NbExp=3; IntAct=EBI-1383852, EBI-12014286; CC P54646; Q9NQX0: PRDM6; NbExp=3; IntAct=EBI-1383852, EBI-11320284; CC P54646; Q9Y478: PRKAB1; NbExp=8; IntAct=EBI-1383852, EBI-719769; CC P54646; O43741: PRKAB2; NbExp=14; IntAct=EBI-1383852, EBI-1053424; CC P54646; P54619: PRKAG1; NbExp=13; IntAct=EBI-1383852, EBI-1181439; CC P54646; P31321: PRKAR1B; NbExp=3; IntAct=EBI-1383852, EBI-2805516; CC P54646; P41219: PRPH; NbExp=3; IntAct=EBI-1383852, EBI-752074; CC P54646; Q86YV0: RASAL3; NbExp=3; IntAct=EBI-1383852, EBI-3437896; CC P54646; Q93062: RBPMS; NbExp=3; IntAct=EBI-1383852, EBI-740322; CC P54646; Q04864-2: REL; NbExp=4; IntAct=EBI-1383852, EBI-10829018; CC P54646; Q8HWS3: RFX6; NbExp=3; IntAct=EBI-1383852, EBI-746118; CC P54646; Q9Y3C5: RNF11; NbExp=3; IntAct=EBI-1383852, EBI-396669; CC P54646; Q7Z5V6-2: SAXO4; NbExp=3; IntAct=EBI-1383852, EBI-12000762; CC P54646; Q9UJW9: SERTAD3; NbExp=3; IntAct=EBI-1383852, EBI-748621; CC P54646; Q15477: SKIC2; NbExp=3; IntAct=EBI-1383852, EBI-373226; CC P54646; Q9H6Q3: SLA2; NbExp=3; IntAct=EBI-1383852, EBI-1222854; CC P54646; Q5JUK2: SOHLH1; NbExp=3; IntAct=EBI-1383852, EBI-12288855; CC P54646; O43609: SPRY1; NbExp=3; IntAct=EBI-1383852, EBI-3866665; CC P54646; Q6ZMT1: STAC2; NbExp=3; IntAct=EBI-1383852, EBI-948802; CC P54646; Q15831: STK11; NbExp=3; IntAct=EBI-1383852, EBI-306838; CC P54646; P15884: TCF4; NbExp=3; IntAct=EBI-1383852, EBI-533224; CC P54646; Q96CG3: TIFA; NbExp=3; IntAct=EBI-1383852, EBI-740711; CC P54646; Q08117: TLE5; NbExp=3; IntAct=EBI-1383852, EBI-717810; CC P54646; Q08117-2: TLE5; NbExp=3; IntAct=EBI-1383852, EBI-11741437; CC P54646; Q15645: TRIP13; NbExp=3; IntAct=EBI-1383852, EBI-358993; CC P54646; Q15654: TRIP6; NbExp=3; IntAct=EBI-1383852, EBI-742327; CC P54646; Q9Y3Q8: TSC22D4; NbExp=3; IntAct=EBI-1383852, EBI-739485; CC P54646; O75385: ULK1; NbExp=2; IntAct=EBI-1383852, EBI-908831; CC P54646; Q9Y6N9-4: USH1C; NbExp=3; IntAct=EBI-1383852, EBI-11523636; CC P54646; Q495M9: USH1G; NbExp=3; IntAct=EBI-1383852, EBI-8601749; CC P54646; Q8N6Y0: USHBP1; NbExp=3; IntAct=EBI-1383852, EBI-739895; CC P54646; Q9UK41-2: VPS28; NbExp=3; IntAct=EBI-1383852, EBI-12146727; CC P54646; Q9H9H4: VPS37B; NbExp=3; IntAct=EBI-1383852, EBI-4400866; CC P54646; Q8N1B4: VPS52; NbExp=3; IntAct=EBI-1383852, EBI-2799833; CC P54646; O76024: WFS1; NbExp=3; IntAct=EBI-1383852, EBI-720609; CC P54646; O00308: WWP2; NbExp=3; IntAct=EBI-1383852, EBI-743923; CC P54646; P62258: YWHAE; NbExp=2; IntAct=EBI-1383852, EBI-356498; CC P54646; Q96BR9: ZBTB8A; NbExp=3; IntAct=EBI-1383852, EBI-742740; CC P54646; Q9H0C1: ZMYND12; NbExp=3; IntAct=EBI-1383852, EBI-12030590; CC P54646; Q9UDV6: ZNF212; NbExp=3; IntAct=EBI-1383852, EBI-1640204; CC P54646; Q8NF99: ZNF397; NbExp=3; IntAct=EBI-1383852, EBI-10213894; CC P54646; Q3MJ62: ZSCAN23; NbExp=3; IntAct=EBI-1383852, EBI-5667532; CC P54646; Q9WTK7: Stk11; Xeno; NbExp=2; IntAct=EBI-1383852, EBI-8627450; CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:Q8BRK8}. Nucleus CC {ECO:0000269|PubMed:15866171}. Note=In response to stress, recruited by CC p53/TP53 to specific promoters. {ECO:0000269|PubMed:15866171}. CC -!- DOMAIN: The AIS (autoinhibitory sequence) region shows some sequence CC similarity with the ubiquitin-associated domains and represses kinase CC activity. {ECO:0000250|UniProtKB:Q13131}. CC -!- PTM: Ubiquitinated. {ECO:0000250|UniProtKB:Q8BRK8}. CC -!- PTM: Phosphorylated at Thr-172 by STK11/LKB1 in complex with STE20- CC related adapter-alpha (STRADA) pseudo kinase and CAB39. Also CC phosphorylated at Thr-172 by CAMKK2; triggered by a rise in CC intracellular calcium ions, without detectable changes in the AMP/ATP CC ratio. CAMKK1 can also phosphorylate Thr-172, but at much lower level. CC Dephosphorylated by protein phosphatase 2A and 2C (PP2A and PP2C). CC Phosphorylated by ULK1; leading to negatively regulate AMPK activity CC and suggesting the existence of a regulatory feedback loop between ULK1 CC and AMPK. Dephosphorylated by PPM1A and PPM1B at Thr-172 (mediated by CC STK11/LKB1). {ECO:0000269|PubMed:15980064, CC ECO:0000269|PubMed:21460634}. CC -!- SIMILARITY: Belongs to the protein kinase superfamily. CAMK Ser/Thr CC protein kinase family. SNF1 subfamily. {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; U06454; AAA64745.1; -; mRNA. DR EMBL; AL035705; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; BC069680; AAH69680.1; -; mRNA. DR EMBL; BC069740; AAH69740.1; -; mRNA. DR EMBL; BC069823; AAH69823.1; -; mRNA. DR CCDS; CCDS605.1; -. DR PIR; S51025; S51025. DR RefSeq; NP_006243.2; NM_006252.3. DR PDB; 2H6D; X-ray; 1.85 A; A=6-279. DR PDB; 2LTU; NMR; -; A=282-339. DR PDB; 2YZA; X-ray; 3.02 A; A=6-279. DR PDB; 3AQV; X-ray; 2.08 A; A=6-279. DR PDB; 4CFE; X-ray; 3.02 A; A/C=1-552. DR PDB; 4CFF; X-ray; 3.92 A; A/C=1-552. DR PDB; 4ZHX; X-ray; 2.99 A; A/C=2-552. DR PDB; 5EZV; X-ray; 2.99 A; A/C=2-347, A/C=397-552. DR PDB; 5ISO; X-ray; 2.63 A; A/C=1-552. DR PDB; 6B1U; X-ray; 2.77 A; A/C=2-552. DR PDB; 6B2E; X-ray; 3.80 A; A=2-552. DR PDB; 6BX6; X-ray; 2.90 A; A=6-279. DR PDB; 7MYJ; X-ray; 2.95 A; A/C=2-552. DR PDBsum; 2H6D; -. DR PDBsum; 2LTU; -. DR PDBsum; 2YZA; -. DR PDBsum; 3AQV; -. DR PDBsum; 4CFE; -. DR PDBsum; 4CFF; -. DR PDBsum; 4ZHX; -. DR PDBsum; 5EZV; -. DR PDBsum; 5ISO; -. DR PDBsum; 6B1U; -. DR PDBsum; 6B2E; -. DR PDBsum; 6BX6; -. DR PDBsum; 7MYJ; -. DR AlphaFoldDB; P54646; -. DR BMRB; P54646; -. DR SMR; P54646; -. DR BioGRID; 111550; 225. DR ComplexPortal; CPX-5787; AMPK complex, alpha2-beta1-gamma1 variant. DR ComplexPortal; CPX-5790; AMPK complex, alpha2-beta2-gamma1 variant. DR ComplexPortal; CPX-5840; AMPK complex, alpha2-beta2-gamma3 variant. DR ComplexPortal; CPX-5843; AMPK complex, alpha2-beta1-gamma3 variant. DR ComplexPortal; CPX-5844; AMPK complex, alpha2-beta1-gamma2 variant. DR ComplexPortal; CPX-5845; AMPK complex, alpha2-beta2-gamma2 variant. DR CORUM; P54646; -. DR DIP; DIP-39796N; -. DR IntAct; P54646; 163. DR MINT; P54646; -. DR STRING; 9606.ENSP00000360290; -. DR BindingDB; P54646; -. DR ChEMBL; CHEMBL2116; -. DR DrugBank; DB00945; Acetylsalicylic acid. DR DrugBank; DB00131; Adenosine phosphate. DR DrugBank; DB12010; Fostamatinib. DR DrugBank; DB00273; Topiramate. DR DrugCentral; P54646; -. DR TCDB; 8.A.104.1.1; the 5'-amp-activated protein kinase (ampk) family. DR GlyConnect; 985; 2 N-Linked glycans (1 site). DR GlyCosmos; P54646; 1 site, 3 glycans. DR GlyGen; P54646; 2 sites, 3 N-linked glycans (1 site), 1 O-linked glycan (1 site). DR iPTMnet; P54646; -. DR PhosphoSitePlus; P54646; -. DR BioMuta; PRKAA2; -. DR DMDM; 20178276; -. DR EPD; P54646; -. DR jPOST; P54646; -. DR MassIVE; P54646; -. DR MaxQB; P54646; -. DR PaxDb; 9606-ENSP00000360290; -. DR PeptideAtlas; P54646; -. DR ProteomicsDB; 56689; -. DR Pumba; P54646; -. DR Antibodypedia; 3399; 991 antibodies from 44 providers. DR DNASU; 5563; -. DR Ensembl; ENST00000371244.9; ENSP00000360290.4; ENSG00000162409.12. DR GeneID; 5563; -. DR KEGG; hsa:5563; -. DR MANE-Select; ENST00000371244.9; ENSP00000360290.4; NM_006252.4; NP_006243.2. DR UCSC; uc001cyk.5; human. DR AGR; HGNC:9377; -. DR CTD; 5563; -. DR DisGeNET; 5563; -. DR GeneCards; PRKAA2; -. DR HGNC; HGNC:9377; PRKAA2. DR HPA; ENSG00000162409; Tissue enhanced (heart muscle, skeletal muscle, tongue). DR MIM; 600497; gene. DR neXtProt; NX_P54646; -. DR OpenTargets; ENSG00000162409; -. DR PharmGKB; PA33745; -. DR VEuPathDB; HostDB:ENSG00000162409; -. DR eggNOG; KOG0583; Eukaryota. DR GeneTree; ENSGT00940000156945; -. DR HOGENOM; CLU_000288_59_3_1; -. DR InParanoid; P54646; -. DR OrthoDB; 5475340at2759; -. DR PhylomeDB; P54646; -. DR TreeFam; TF314032; -. DR BRENDA; 2.7.11.1; 2681. DR BRENDA; 2.7.11.31; 2681. DR PathwayCommons; P54646; -. DR Reactome; R-HSA-1445148; Translocation of SLC2A4 (GLUT4) to the plasma membrane. DR Reactome; R-HSA-1632852; Macroautophagy. DR Reactome; R-HSA-163680; AMPK inhibits chREBP transcriptional activation activity. DR Reactome; R-HSA-200425; Carnitine metabolism. DR Reactome; R-HSA-2151209; Activation of PPARGC1A (PGC-1alpha) by phosphorylation. DR Reactome; R-HSA-380972; Energy dependent regulation of mTOR by LKB1-AMPK. DR Reactome; R-HSA-5628897; TP53 Regulates Metabolic Genes. DR Reactome; R-HSA-6804756; Regulation of TP53 Activity through Phosphorylation. DR Reactome; R-HSA-9613354; Lipophagy. DR Reactome; R-HSA-9619483; Activation of AMPK downstream of NMDARs. DR Reactome; R-HSA-9759194; Nuclear events mediated by NFE2L2. DR SignaLink; P54646; -. DR SIGNOR; P54646; -. DR BioGRID-ORCS; 5563; 16 hits in 1188 CRISPR screens. DR ChiTaRS; PRKAA2; human. DR EvolutionaryTrace; P54646; -. DR GeneWiki; PRKAA2; -. DR GenomeRNAi; 5563; -. DR Pharos; P54646; Tchem. DR PRO; PR:P54646; -. DR Proteomes; UP000005640; Chromosome 1. DR RNAct; P54646; Protein. DR Bgee; ENSG00000162409; Expressed in skeletal muscle tissue of rectus abdominis and 181 other cell types or tissues. DR ExpressionAtlas; P54646; baseline and differential. DR GO; GO:0030424; C:axon; ISS:ARUK-UCL. DR GO; GO:0010494; C:cytoplasmic stress granule; ISS:ARUK-UCL. DR GO; GO:0005829; C:cytosol; TAS:Reactome. DR GO; GO:0030425; C:dendrite; ISS:ARUK-UCL. DR GO; GO:0005794; C:Golgi apparatus; IDA:HPA. DR GO; GO:0043025; C:neuronal cell body; ISS:ARUK-UCL. DR GO; GO:0016607; C:nuclear speck; IDA:HPA. DR GO; GO:0005654; C:nucleoplasm; TAS:Reactome. DR GO; GO:0031588; C:nucleotide-activated protein kinase complex; IPI:ComplexPortal. DR GO; GO:0005634; C:nucleus; IDA:ComplexPortal. DR GO; GO:0050405; F:[acetyl-CoA carboxylase] kinase activity; IEA:UniProtKB-EC. DR GO; GO:0047322; F:[hydroxymethylglutaryl-CoA reductase (NADPH)] kinase activity; IEA:UniProtKB-EC. DR GO; GO:0004679; F:AMP-activated protein kinase activity; IDA:UniProtKB. DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW. DR GO; GO:0003682; F:chromatin binding; ISS:UniProtKB. DR GO; GO:0140823; F:histone H2BS36 kinase activity; ISS:UniProtKB. DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW. DR GO; GO:0004672; F:protein kinase activity; TAS:ProtInc. DR GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA. DR GO; GO:0004674; F:protein serine/threonine kinase activity; IDA:UniProtKB. DR GO; GO:0004712; F:protein serine/threonine/tyrosine kinase activity; IDA:MGI. DR GO; GO:0006914; P:autophagy; IEA:UniProtKB-KW. DR GO; GO:0071277; P:cellular response to calcium ion; ISS:ARUK-UCL. DR GO; GO:0042149; P:cellular response to glucose starvation; IDA:UniProtKB. DR GO; GO:0071333; P:cellular response to glucose stimulus; ISS:ARUK-UCL. DR GO; GO:0031669; P:cellular response to nutrient levels; IDA:ComplexPortal. DR GO; GO:0034599; P:cellular response to oxidative stress; ISS:ARUK-UCL. DR GO; GO:0071380; P:cellular response to prostaglandin E stimulus; IEA:Ensembl. DR GO; GO:0071466; P:cellular response to xenobiotic stimulus; IEA:Ensembl. DR GO; GO:0006695; P:cholesterol biosynthetic process; IEA:UniProtKB-KW. DR GO; GO:0097009; P:energy homeostasis; ISS:UniProtKB. DR GO; GO:0006633; P:fatty acid biosynthetic process; IEA:UniProtKB-KW. DR GO; GO:0055089; P:fatty acid homeostasis; ISS:UniProtKB. DR GO; GO:0042593; P:glucose homeostasis; ISS:UniProtKB. DR GO; GO:0035556; P:intracellular signal transduction; IBA:GO_Central. DR GO; GO:0008610; P:lipid biosynthetic process; ISS:UniProtKB. DR GO; GO:1905691; P:lipid droplet disassembly; IDA:UniProtKB. DR GO; GO:0043066; P:negative regulation of apoptotic process; ISS:UniProtKB. DR GO; GO:0010629; P:negative regulation of gene expression; ISS:ARUK-UCL. DR GO; GO:1903944; P:negative regulation of hepatocyte apoptotic process; IDA:UniProt. DR GO; GO:0032007; P:negative regulation of TOR signaling; ISS:UniProtKB. DR GO; GO:1904262; P:negative regulation of TORC1 signaling; IDA:UniProtKB. DR GO; GO:1904428; P:negative regulation of tubulin deacetylation; ISS:ARUK-UCL. DR GO; GO:0010508; P:positive regulation of autophagy; ISS:UniProtKB. DR GO; GO:0045821; P:positive regulation of glycolytic process; ISS:UniProtKB. DR GO; GO:0016239; P:positive regulation of macroautophagy; TAS:ParkinsonsUK-UCL. DR GO; GO:2000758; P:positive regulation of peptidyl-lysine acetylation; ISS:ARUK-UCL. DR GO; GO:1903829; P:positive regulation of protein localization; ISS:ARUK-UCL. DR GO; GO:1990044; P:protein localization to lipid droplet; IDA:UniProtKB. DR GO; GO:0006468; P:protein phosphorylation; TAS:ProtInc. DR GO; GO:0042752; P:regulation of circadian rhythm; ISS:UniProtKB. DR GO; GO:0016241; P:regulation of macroautophagy; ISS:UniProtKB. DR GO; GO:0070507; P:regulation of microtubule cytoskeleton organization; ISS:ARUK-UCL. DR GO; GO:0062028; P:regulation of stress granule assembly; IEA:Ensembl. DR GO; GO:0014850; P:response to muscle activity; IEA:Ensembl. DR GO; GO:0048511; P:rhythmic process; IEA:UniProtKB-KW. DR GO; GO:0007165; P:signal transduction; TAS:ProtInc. DR GO; GO:0016055; P:Wnt signaling pathway; IEA:UniProtKB-KW. DR CDD; cd12200; AMPKA2_C; 1. DR CDD; cd14079; STKc_AMPK_alpha; 1. DR CDD; cd14404; UBA_AID_AAPK2; 1. DR Gene3D; 1.10.8.10; DNA helicase RuvA subunit, C-terminal domain; 1. DR Gene3D; 3.30.310.80; Kinase associated domain 1, KA1; 1. DR Gene3D; 1.10.510.10; Transferase(Phosphotransferase) domain 1; 1. DR IDEAL; IID00661; -. DR InterPro; IPR032270; AMPK_C. DR InterPro; IPR039148; AMPKA2_C. DR InterPro; IPR028375; KA1/Ssp2_C. DR InterPro; IPR011009; Kinase-like_dom_sf. DR InterPro; IPR049020; PRKAA1/2_AID. DR InterPro; IPR028783; PRKAA2. DR InterPro; IPR000719; Prot_kinase_dom. DR InterPro; IPR017441; Protein_kinase_ATP_BS. DR InterPro; IPR008271; Ser/Thr_kinase_AS. DR PANTHER; PTHR24346; MAP/MICROTUBULE AFFINITY-REGULATING KINASE; 1. DR PANTHER; PTHR24346:SF82; SERINE_THREONINE-PROTEIN KINASE MARK-A-RELATED; 1. DR Pfam; PF16579; AdenylateSensor; 1. DR Pfam; PF21147; AMPK_alpha_AID; 1. DR Pfam; PF00069; Pkinase; 1. DR SMART; SM00220; S_TKc; 1. DR SUPFAM; SSF103243; KA1-like; 1. DR SUPFAM; SSF56112; Protein kinase-like (PK-like); 1. DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1. DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1. DR PROSITE; PS00108; PROTEIN_KINASE_ST; 1. DR Genevisible; P54646; HS. PE 1: Evidence at protein level; KW 3D-structure; ATP-binding; Autophagy; Biological rhythms; KW Cholesterol biosynthesis; Cholesterol metabolism; Chromatin regulator; KW Cytoplasm; Fatty acid biosynthesis; Fatty acid metabolism; Kinase; KW Lipid biosynthesis; Lipid metabolism; Magnesium; Metal-binding; KW Nucleotide-binding; Nucleus; Phosphoprotein; Reference proteome; KW Serine/threonine-protein kinase; Steroid biosynthesis; Steroid metabolism; KW Sterol biosynthesis; Sterol metabolism; Transcription; KW Transcription regulation; Transferase; Ubl conjugation; KW Wnt signaling pathway. FT CHAIN 1..552 FT /note="5'-AMP-activated protein kinase catalytic subunit FT alpha-2" FT /id="PRO_0000085594" FT DOMAIN 16..268 FT /note="Protein kinase" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT REGION 291..376 FT /note="AIS" FT /evidence="ECO:0000250|UniProtKB:Q13131" FT REGION 477..521 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 498..521 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT ACT_SITE 139 FT /note="Proton acceptor" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159, FT ECO:0000255|PROSITE-ProRule:PRU10027" FT BINDING 22..30 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT BINDING 45 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT MOD_RES 172 FT /note="Phosphothreonine; by LKB1 and CaMKK2" FT /evidence="ECO:0000269|PubMed:15980064, FT ECO:0000269|PubMed:24767988, ECO:0000269|PubMed:28552616" FT MOD_RES 258 FT /note="Phosphothreonine" FT /evidence="ECO:0000250|UniProtKB:Q09137" FT MOD_RES 377 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18691976, FT ECO:0007744|PubMed:19369195, ECO:0007744|PubMed:23186163" FT MOD_RES 491 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q09137" FT VARIANT 371 FT /note="P -> T (in breast cancer samples; infiltrating FT ductal carcinoma; somatic mutation)" FT /evidence="ECO:0000269|PubMed:16959974, FT ECO:0000269|PubMed:17344846" FT /id="VAR_035623" FT VARIANT 407 FT /note="R -> Q (in a gastric adenocarcinoma sample; somatic FT mutation)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_040355" FT VARIANT 523 FT /note="S -> G (in a breast cancer sample; somatic FT mutation)" FT /evidence="ECO:0000269|PubMed:16959974" FT /id="VAR_035624" FT MUTAGEN 45 FT /note="K->R: Complete loss of kinase activity." FT /evidence="ECO:0000305|PubMed:36017701" FT MUTAGEN 172 FT /note="T->A: Loss of ARF6 activation. Loss of interaction FT with ACSS2." FT /evidence="ECO:0000269|PubMed:28552616, FT ECO:0000269|PubMed:36017701" FT MUTAGEN 172 FT /note="T->D: Phosphomimetic mutant." FT /evidence="ECO:0000269|PubMed:21543851" FT CONFLICT 180 FT /note="A -> T (in Ref. 1; AAA64745)" FT /evidence="ECO:0000305" FT CONFLICT 271 FT /note="D -> G (in Ref. 1; AAA64745)" FT /evidence="ECO:0000305" FT CONFLICT 403..404 FT /note="HL -> RQ (in Ref. 1; AAA64745)" FT /evidence="ECO:0000305" FT STRAND 16..24 FT /evidence="ECO:0007829|PDB:2H6D" FT STRAND 26..35 FT /evidence="ECO:0007829|PDB:2H6D" FT TURN 36..38 FT /evidence="ECO:0007829|PDB:2H6D" FT STRAND 41..48 FT /evidence="ECO:0007829|PDB:2H6D" FT HELIX 49..54 FT /evidence="ECO:0007829|PDB:2H6D" FT HELIX 58..69 FT /evidence="ECO:0007829|PDB:2H6D" FT STRAND 79..84 FT /evidence="ECO:0007829|PDB:2H6D" FT STRAND 86..94 FT /evidence="ECO:0007829|PDB:2H6D" FT HELIX 101..108 FT /evidence="ECO:0007829|PDB:2H6D" FT HELIX 113..133 FT /evidence="ECO:0007829|PDB:2H6D" FT HELIX 142..144 FT /evidence="ECO:0007829|PDB:2H6D" FT STRAND 145..147 FT /evidence="ECO:0007829|PDB:2H6D" FT STRAND 153..155 FT /evidence="ECO:0007829|PDB:2H6D" FT HELIX 160..162 FT /evidence="ECO:0007829|PDB:2H6D" FT HELIX 177..179 FT /evidence="ECO:0007829|PDB:5ISO" FT HELIX 183..185 FT /evidence="ECO:0007829|PDB:2H6D" FT HELIX 192..209 FT /evidence="ECO:0007829|PDB:2H6D" FT HELIX 219..228 FT /evidence="ECO:0007829|PDB:2H6D" FT STRAND 235..237 FT /evidence="ECO:0007829|PDB:6BX6" FT HELIX 239..248 FT /evidence="ECO:0007829|PDB:2H6D" FT HELIX 253..255 FT /evidence="ECO:0007829|PDB:2H6D" FT HELIX 259..264 FT /evidence="ECO:0007829|PDB:2H6D" FT HELIX 266..269 FT /evidence="ECO:0007829|PDB:2H6D" FT HELIX 274..276 FT /evidence="ECO:0007829|PDB:2H6D" FT HELIX 283..286 FT /evidence="ECO:0007829|PDB:5ISO" FT HELIX 290..299 FT /evidence="ECO:0007829|PDB:5ISO" FT HELIX 304..312 FT /evidence="ECO:0007829|PDB:5ISO" FT HELIX 319..335 FT /evidence="ECO:0007829|PDB:5ISO" FT HELIX 338..341 FT /evidence="ECO:0007829|PDB:5ISO" FT STRAND 403..408 FT /evidence="ECO:0007829|PDB:5ISO" FT HELIX 412..426 FT /evidence="ECO:0007829|PDB:5ISO" FT STRAND 429..434 FT /evidence="ECO:0007829|PDB:5ISO" FT STRAND 437..443 FT /evidence="ECO:0007829|PDB:5ISO" FT TURN 445..447 FT /evidence="ECO:0007829|PDB:5ISO" FT STRAND 450..459 FT /evidence="ECO:0007829|PDB:5ISO" FT STRAND 461..463 FT /evidence="ECO:0007829|PDB:5ISO" FT STRAND 465..472 FT /evidence="ECO:0007829|PDB:5ISO" FT HELIX 535..549 FT /evidence="ECO:0007829|PDB:5ISO" SQ SEQUENCE 552 AA; 62320 MW; C46AAFC1D5104975 CRC64; MAEKQKHDGR VKIGHYVLGD TLGVGTFGKV KIGEHQLTGH KVAVKILNRQ KIRSLDVVGK IKREIQNLKL FRHPHIIKLY QVISTPTDFF MVMEYVSGGE LFDYICKHGR VEEMEARRLF QQILSAVDYC HRHMVVHRDL KPENVLLDAH MNAKIADFGL SNMMSDGEFL RTSCGSPNYA APEVISGRLY AGPEVDIWSC GVILYALLCG TLPFDDEHVP TLFKKIRGGV FYIPEYLNRS VATLLMHMLQ VDPLKRATIK DIREHEWFKQ DLPSYLFPED PSYDANVIDD EAVKEVCEKF ECTESEVMNS LYSGDPQDQL AVAYHLIIDN RRIMNQASEF YLASSPPSGS FMDDSAMHIP PGLKPHPERM PPLIADSPKA RCPLDALNTT KPKSLAVKKA KWHLGIRSQS KPYDIMAEVY RAMKQLDFEW KVVNAYHLRV RRKNPVTGNY VKMSLQLYLV DNRSYLLDFK SIDDEVVEQR SGSSTPQRSC SAAGLHRPRS SFDSTTAESH SLSGSLTGSL TGSTLSSVSP RLGSHTMDFF EMCASLITTL AR //