AAPK2_HUMAN
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 03-AUG-2022, entry version 214.
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:32029622};
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 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 [32]
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 [33]
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 [34]
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 [35]
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 [36]
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 TSC2, RPTOR and ATG1/ULK1: in response to nutrient limitation,
CC negatively regulates the mTORC1 complex by phosphorylating RPTOR
CC component of the mTORC1 complex and by phosphorylating and activating
CC TSC2 (PubMed:14651849, PubMed:20160076, PubMed:21205641). In response
CC to nutrient limitation, promotes autophagy by phosphorylating and
CC activating ATG1/ULK1 (PubMed:21205641). In that process also activates
CC WDR45/WIPI4 (PubMed:28561066). Phosphorylates CASP6, thereby preventing
CC its autoprocessing and subsequent activation (PubMed:32029622). AMPK
CC also acts as a regulator of circadian rhythm by mediating
CC phosphorylation of CRY1, leading to destabilize it (By similarity). May
CC regulate the Wnt signaling pathway by phosphorylating CTNNB1, leading
CC to stabilize it (By similarity). Also acts as a regulator of cellular
CC polarity by remodeling the actin cytoskeleton; probably by indirectly
CC activating myosin (PubMed:17486097). Also phosphorylates CFTR, EEF2K,
CC KLC1, NOS3 and SLC12A1 (PubMed:12519745, PubMed:20074060). 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 (By similarity). Can inhibit the non-autophagy
CC complex by phosphorylating PIK3C3 and can activate the pro-autophagy
CC complex by phosphorylating BECN1 (By similarity).
CC {ECO:0000250|UniProtKB:Q09137, 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:32029622,
CC ECO:0000269|PubMed:34077757, ECO:0000269|PubMed:7959015,
CC ECO:0000303|PubMed:17307971, 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:32029622};
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; EC=2.7.11.27;
CC 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 {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; 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; 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=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; 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; O76024: WFS1; NbExp=3; IntAct=EBI-1383852, EBI-720609;
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|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}.
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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 AlphaFoldDB; P54646; -.
DR BMRB; P54646; -.
DR SMR; P54646; -.
DR BioGRID; 111550; 192.
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; 160.
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 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; P54646; -.
DR PeptideAtlas; P54646; -.
DR PRIDE; P54646; -.
DR ProteomicsDB; 56689; -.
DR Antibodypedia; 3399; 843 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 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 OrthoDB; 1127668at2759; -.
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 SignaLink; P54646; -.
DR SIGNOR; P54646; -.
DR BioGRID-ORCS; 5563; 14 hits in 1105 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 179 other tissues.
DR ExpressionAtlas; P54646; baseline and differential.
DR Genevisible; P54646; HS.
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: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: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:0006325; P:chromatin organization; 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: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: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; IBA:GO_Central.
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; cd14404; UBA_AID_AAPK2; 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; IPR028783; PRKAA2.
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; 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"
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 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: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
