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Database: UniProt
Entry: P54646
LinkDB: P54646
Original site: P54646 
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   17-JUN-2020, entry version 204.
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:0000250|UniProtKB:Q09137};
DE   AltName: Full=Acetyl-CoA carboxylase kinase;
DE            Short=ACACA kinase;
DE            EC=2.7.11.27 {ECO:0000250|UniProtKB:Q09137};
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.
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   [31]
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   [32]
RP   X-RAY CRYSTALLOGRAPHY (2.08 ANGSTROMS) OF 6-279 OF MUTANT THR-172 IN
RP   COMPLEX WITH COMPOUND C, AND ACTIVITY REGULATION.
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   [33]
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   [34]
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. In response to reduction of intracellular
CC       ATP levels, AMPK activates energy-producing pathways and inhibits
CC       energy-consuming processes: inhibits protein, carbohydrate and lipid
CC       biosynthesis, as well as cell growth and proliferation. AMPK acts via
CC       direct phosphorylation of metabolic enzymes, and by longer-term effects
CC       via phosphorylation of transcription regulators. Also acts as a
CC       regulator of cellular polarity by remodeling the actin cytoskeleton;
CC       probably by indirectly activating myosin. 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. Regulates
CC       insulin-signaling and glycolysis by phosphorylating IRS1, PFKFB2 and
CC       PFKFB3. Involved in insulin receptor/INSR internalization
CC       (PubMed:25687571). AMPK stimulates glucose uptake in muscle by
CC       increasing the translocation of the glucose transporter SLC2A4/GLUT4 to
CC       the plasma membrane, possibly by mediating phosphorylation of
CC       TBC1D4/AS160. Regulates transcription and chromatin structure by
CC       phosphorylating transcription regulators involved in energy metabolism
CC       such as CRTC2/TORC2, FOXO3, histone H2B, HDAC5, MEF2C, MLXIPL/ChREBP,
CC       EP300, HNF4A, p53/TP53, SREBF1, SREBF2 and PPARGC1A. Acts as a key
CC       regulator of glucose homeostasis in liver by phosphorylating
CC       CRTC2/TORC2, leading to CRTC2/TORC2 sequestration in the cytoplasm. In
CC       response to stress, phosphorylates 'Ser-36' of histone H2B (H2BS36ph),
CC       leading to promote transcription. Acts as a key regulator of cell
CC       growth and proliferation by phosphorylating TSC2, RPTOR and ATG1/ULK1:
CC       in response to nutrient limitation, negatively regulates the mTORC1
CC       complex by phosphorylating RPTOR component of the mTORC1 complex and by
CC       phosphorylating and activating TSC2. In response to nutrient
CC       limitation, promotes autophagy by phosphorylating and activating
CC       ATG1/ULK1. In that process also activates WDR45 (PubMed:28561066). AMPK
CC       also acts as a regulator of circadian rhythm by mediating
CC       phosphorylation of CRY1, leading to destabilize it. May regulate the
CC       Wnt signaling pathway by phosphorylating CTNNB1, leading to stabilize
CC       it. Also phosphorylates CFTR, EEF2K, KLC1, NOS3 and SLC12A1. Plays an
CC       important role in the differential regulation of pro-autophagy
CC       (composed of PIK3C3, BECN1, PIK3R4 and UVRAG or ATG14) and non-
CC       autophagy (composed of PIK3C3, BECN1 and PIK3R4) complexes, in response
CC       to glucose starvation. Can inhibit the non-autophagy complex by
CC       phosphorylating PIK3C3 and can activate the pro-autophagy complex by
CC       phosphorylating BECN1 (By similarity). {ECO:0000250|UniProtKB:Q8BRK8,
CC       ECO:0000269|PubMed:11518699, ECO:0000269|PubMed:11554766,
CC       ECO:0000269|PubMed:12519745, ECO:0000269|PubMed:14651849,
CC       ECO:0000269|PubMed:15866171, ECO:0000269|PubMed:17486097,
CC       ECO:0000269|PubMed:17711846, ECO:0000269|PubMed:18184930,
CC       ECO:0000269|PubMed:20074060, ECO:0000269|PubMed:20160076,
CC       ECO:0000269|PubMed:21205641, ECO:0000269|PubMed:25687571,
CC       ECO:0000269|PubMed:28561066, ECO:0000269|PubMed:7959015}.
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:0000250|UniProtKB:Q09137};
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=[acetyl-CoA carboxylase]-L-serine + ATP = [acetyl-CoA
CC         carboxylase]-O-phospho-L-serine + ADP + H(+); 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; EC=2.7.11.27;
CC         Evidence={ECO:0000250|UniProtKB:Q09137};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=[3-hydroxy-3-methylglutaryl-coenzyme A reductase]-L-serine +
CC         ATP = [3-hydroxy-3-methylglutaryl-coenzyme A reductase]-O-phospho-L-
CC         serine + ADP + H(+); Xref=Rhea:RHEA:23172, Rhea:RHEA-COMP:13692,
CC         Rhea:RHEA-COMP:13693, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999,
CC         ChEBI:CHEBI:30616, ChEBI:CHEBI:83421, ChEBI:CHEBI:456216;
CC         EC=2.7.11.31; Evidence={ECO:0000250|UniProtKB:Q09137};
CC   -!- COFACTOR:
CC       Name=Mg(2+); Xref=ChEBI:CHEBI:18420; Evidence={ECO:0000250};
CC   -!- ACTIVITY REGULATION: Activated by phosphorylation on Thr-172. Binding
CC       of AMP to non-catalytic gamma subunit (PRKAG1, PRKAG2 or PRKAG3)
CC       results in allosteric activation, inducing phosphorylation on Thr-172.
CC       AMP-binding to gamma subunit also sustains activity by preventing
CC       dephosphorylation of Thr-172. ADP also stimulates Thr-172
CC       phosphorylation, without stimulating already phosphorylated AMPK. ATP
CC       promotes dephosphorylation of Thr-172, rendering the enzyme inactive.
CC       Under physiological conditions AMPK mainly exists in its inactive form
CC       in complex with ATP, which is much more abundant than AMP. AMPK is
CC       activated by antihyperglycemic drug metformin, a drug prescribed to
CC       patients with type 2 diabetes: in vivo, metformin seems to mainly
CC       inhibit liver gluconeogenesis. However, metformin can be used to
CC       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). Interacts with FNIP1 and FNIP2.
CC       Associates with internalized insulin receptor/INSR complexes on
CC       Golgi/endosomal membranes; PRKAA2/AMPK2 together with ATIC and
CC       HACD3/PTPLAD1 is proposed to be part of a signaling network regulating
CC       INSR autophosphorylation and endocytosis (PubMed:25687571).
CC       {ECO:0000269|PubMed:21543851, ECO:0000269|PubMed:25687571}.
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; 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; 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; 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; Q9NQM4: PIH1D3; NbExp=3; IntAct=EBI-1383852, EBI-10239299;
CC       P54646; Q494U1-3: PLEKHN1; NbExp=3; IntAct=EBI-1383852, EBI-12014286;
CC       P54646; Q7Z5V6-2: PPP1R32; NbExp=3; IntAct=EBI-1383852, EBI-12000762;
CC       P54646; Q9NQX0: PRDM6; NbExp=3; IntAct=EBI-1383852, EBI-11320284;
CC       P54646; Q9Y478: PRKAB1; NbExp=7; IntAct=EBI-1383852, EBI-719769;
CC       P54646; O43741: PRKAB2; NbExp=12; IntAct=EBI-1383852, EBI-1053424;
CC       P54646; P54619: PRKAG1; NbExp=12; 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; Q9UJW9: SERTAD3; NbExp=3; IntAct=EBI-1383852, EBI-748621;
CC       P54646; Q15477: SKIV2L; 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; O00308: WWP2; NbExp=3; IntAct=EBI-1383852, EBI-743923;
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}. Nucleus
CC       {ECO:0000269|PubMed:15866171}. Note=In response to stress, recruited by
CC       p53/TP53 to specific promoters.
CC   -!- DOMAIN: The AIS (autoinhibitory sequence) region shows some sequence
CC       similarity with the ubiquitin-associated domains and represses kinase
CC       activity.
CC   -!- PTM: Ubiquitinated. {ECO:0000250}.
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}.
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   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   SMR; P54646; -.
DR   BioGRID; 111550; 92.
DR   CORUM; P54646; -.
DR   DIP; DIP-39796N; -.
DR   IntAct; P54646; 138.
DR   MINT; P54646; -.
DR   STRING; 9606.ENSP00000360290; -.
DR   BindingDB; P54646; -.
DR   ChEMBL; CHEMBL2116; -.
DR   DrugBank; DB00945; Acetylsalicylic acid.
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; -.
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; P54646; -.
DR   PeptideAtlas; P54646; -.
DR   PRIDE; P54646; -.
DR   ProteomicsDB; 56689; -.
DR   Antibodypedia; 3399; 782 antibodies.
DR   DNASU; 5563; -.
DR   Ensembl; ENST00000371244; ENSP00000360290; ENSG00000162409.
DR   GeneID; 5563; -.
DR   KEGG; hsa:5563; -.
DR   UCSC; uc001cyk.5; human.
DR   CTD; 5563; -.
DR   DisGeNET; 5563; -.
DR   EuPathDB; HostDB:ENSG00000162409.10; -.
DR   GeneCards; PRKAA2; -.
DR   HGNC; HGNC:9377; PRKAA2.
DR   HPA; ENSG00000162409; Tissue enhanced (heart muscle, skeletal muscle).
DR   MIM; 600497; gene.
DR   neXtProt; NX_P54646; -.
DR   OpenTargets; ENSG00000162409; -.
DR   PharmGKB; PA33745; -.
DR   eggNOG; KOG0586; Eukaryota.
DR   eggNOG; ENOG410XNQ0; LUCA.
DR   GeneTree; ENSGT00940000156945; -.
DR   HOGENOM; CLU_000288_59_3_1; -.
DR   KO; K07198; -.
DR   OMA; TMGYDRD; -.
DR   OrthoDB; 1127668at2759; -.
DR   PhylomeDB; P54646; -.
DR   TreeFam; TF314032; -.
DR   BRENDA; 2.7.11.1; 2681.
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   SignaLink; P54646; -.
DR   SIGNOR; P54646; -.
DR   BioGRID-ORCS; 5563; 5 hits in 816 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 biceps brachii and 207 other tissues.
DR   ExpressionAtlas; P54646; baseline and differential.
DR   Genevisible; P54646; HS.
DR   GO; GO:0030424; C:axon; ISS:ARUK-UCL.
DR   GO; GO:0005623; C:cell; IEA:GOC.
DR   GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
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:0005634; C:nucleus; IBA:GO_Central.
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:0035174; F:histone serine 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:0004674; F:protein serine/threonine kinase activity; ISS:UniProtKB.
DR   GO; GO:0004712; F:protein serine/threonine/tyrosine kinase activity; IDA:MGI.
DR   GO; GO:0006853; P:carnitine shuttle; TAS:Reactome.
DR   GO; GO:0007050; P:cell cycle arrest; TAS:Reactome.
DR   GO; GO:0071277; P:cellular response to calcium ion; ISS:ARUK-UCL.
DR   GO; GO:0035690; P:cellular response to drug; IEA:Ensembl.
DR   GO; GO:0042149; P:cellular response to glucose starvation; ISS:UniProtKB.
DR   GO; GO:0071333; P:cellular response to glucose stimulus; ISS:ARUK-UCL.
DR   GO; GO:0031669; P:cellular response to nutrient levels; ISS:UniProtKB.
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: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:0016236; P:macroautophagy; TAS:Reactome.
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:0032007; P:negative regulation of TOR signaling; ISS: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:1903829; P:positive regulation of cellular protein localization; ISS:ARUK-UCL.
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:0006468; P:protein phosphorylation; IBA:GO_Central.
DR   GO; GO:0042752; P:regulation of circadian rhythm; ISS:UniProtKB.
DR   GO; GO:0042304; P:regulation of fatty acid biosynthetic process; TAS:Reactome.
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:1901796; P:regulation of signal transduction by p53 class mediator; TAS:Reactome.
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   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; IPR000719; Prot_kinase_dom.
DR   InterPro; IPR017441; Protein_kinase_ATP_BS.
DR   InterPro; IPR008271; Ser/Thr_kinase_AS.
DR   Pfam; PF16579; AdenylateSensor; 1.
DR   Pfam; PF00069; Pkinase; 1.
DR   SMART; SM00220; S_TKc; 1.
DR   SUPFAM; SSF103243; SSF103243; 1.
DR   SUPFAM; SSF56112; SSF56112; 1.
DR   PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR   PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR   PROSITE; PS00108; PROTEIN_KINASE_ST; 1.
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; Polymorphism;
KW   Reference proteome; Serine/threonine-protein kinase; Steroid biosynthesis;
KW   Steroid metabolism; 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   NP_BIND         22..30
FT                   /note="ATP"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT   REGION          291..376
FT                   /note="AIS"
FT                   /evidence="ECO:0000250"
FT   ACT_SITE        139
FT                   /note="Proton acceptor"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT                   ECO:0000255|PROSITE-ProRule:PRU10027"
FT   BINDING         45
FT                   /note="ATP"
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"
FT   MOD_RES         258
FT                   /note="Phosphothreonine"
FT                   /evidence="ECO:0000250|UniProtKB:Q09137"
FT   MOD_RES         377
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000244|PubMed:18691976,
FT                   ECO:0000244|PubMed:19369195, ECO:0000244|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         172
FT                   /note="T->D: Phosphomimetic mutant."
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:0000244|PDB:2H6D"
FT   STRAND          26..35
FT                   /evidence="ECO:0000244|PDB:2H6D"
FT   TURN            36..38
FT                   /evidence="ECO:0000244|PDB:2H6D"
FT   STRAND          41..48
FT                   /evidence="ECO:0000244|PDB:2H6D"
FT   HELIX           49..54
FT                   /evidence="ECO:0000244|PDB:2H6D"
FT   HELIX           58..69
FT                   /evidence="ECO:0000244|PDB:2H6D"
FT   STRAND          79..84
FT                   /evidence="ECO:0000244|PDB:2H6D"
FT   STRAND          86..94
FT                   /evidence="ECO:0000244|PDB:2H6D"
FT   HELIX           101..108
FT                   /evidence="ECO:0000244|PDB:2H6D"
FT   HELIX           113..133
FT                   /evidence="ECO:0000244|PDB:2H6D"
FT   HELIX           142..144
FT                   /evidence="ECO:0000244|PDB:2H6D"
FT   STRAND          145..147
FT                   /evidence="ECO:0000244|PDB:2H6D"
FT   STRAND          153..155
FT                   /evidence="ECO:0000244|PDB:2H6D"
FT   HELIX           160..162
FT                   /evidence="ECO:0000244|PDB:2H6D"
FT   HELIX           177..179
FT                   /evidence="ECO:0000244|PDB:5ISO"
FT   HELIX           183..185
FT                   /evidence="ECO:0000244|PDB:2H6D"
FT   HELIX           192..209
FT                   /evidence="ECO:0000244|PDB:2H6D"
FT   HELIX           219..228
FT                   /evidence="ECO:0000244|PDB:2H6D"
FT   STRAND          235..237
FT                   /evidence="ECO:0000244|PDB:6BX6"
FT   HELIX           239..248
FT                   /evidence="ECO:0000244|PDB:2H6D"
FT   HELIX           253..255
FT                   /evidence="ECO:0000244|PDB:2H6D"
FT   HELIX           259..264
FT                   /evidence="ECO:0000244|PDB:2H6D"
FT   HELIX           266..269
FT                   /evidence="ECO:0000244|PDB:2H6D"
FT   HELIX           274..276
FT                   /evidence="ECO:0000244|PDB:2H6D"
FT   HELIX           283..286
FT                   /evidence="ECO:0000244|PDB:5ISO"
FT   HELIX           290..299
FT                   /evidence="ECO:0000244|PDB:5ISO"
FT   HELIX           304..312
FT                   /evidence="ECO:0000244|PDB:5ISO"
FT   HELIX           319..335
FT                   /evidence="ECO:0000244|PDB:5ISO"
FT   HELIX           338..341
FT                   /evidence="ECO:0000244|PDB:5ISO"
FT   STRAND          403..408
FT                   /evidence="ECO:0000244|PDB:5ISO"
FT   HELIX           412..426
FT                   /evidence="ECO:0000244|PDB:5ISO"
FT   STRAND          429..434
FT                   /evidence="ECO:0000244|PDB:5ISO"
FT   STRAND          437..443
FT                   /evidence="ECO:0000244|PDB:5ISO"
FT   TURN            445..447
FT                   /evidence="ECO:0000244|PDB:5ISO"
FT   STRAND          450..459
FT                   /evidence="ECO:0000244|PDB:5ISO"
FT   STRAND          461..463
FT                   /evidence="ECO:0000244|PDB:5ISO"
FT   STRAND          465..472
FT                   /evidence="ECO:0000244|PDB:5ISO"
FT   HELIX           535..549
FT                   /evidence="ECO:0000244|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
//
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