RBCC Red Blood Cell Collection

PRKAA1 (AMPK1) [Confidence: low (only semi-automatic identification from reviews)]
5'-AMP-activated protein kinase catalytic subunit alpha-1; AMPK subunit alpha-1; 2.7.11.1 (Acetyl-CoA carboxylase kinase; ACACA kinase; 2.7.11.27; Hydroxymethylglutaryl-CoA reductase kinase; HMGCR kinase; 2.7.11.31; Tau-protein kinase PRKAA1; 2.7.11.26)
Note: presumably soluble (membrane word is not in UniProt keywords or features)

UniProt Q13131
ID AAPK1_HUMAN Reviewed; 559 AA.
AC Q13131; A8MTQ6; B2R7E1; O00286; Q5D0E1; Q86VS1; Q9UNQ4;
DT 15-JUL-1998, integrated into UniProtKB/Swiss-Prot.
read moreDT 28-JUL-2009, sequence version 4.
DT 22-JAN-2014, entry version 152.
DE RecName: Full=5'-AMP-activated protein kinase catalytic subunit alpha-1;
DE Short=AMPK subunit alpha-1;
DE EC=2.7.11.1;
DE AltName: Full=Acetyl-CoA carboxylase kinase;
DE Short=ACACA kinase;
DE EC=2.7.11.27;
DE AltName: Full=Hydroxymethylglutaryl-CoA reductase kinase;
DE Short=HMGCR kinase;
DE EC=2.7.11.31;
DE AltName: Full=Tau-protein kinase PRKAA1;
DE EC=2.7.11.26;
GN Name=PRKAA1; Synonyms=AMPK1;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15372022; DOI=10.1038/nature02919;
RA Schmutz J., Martin J., Terry A., Couronne O., Grimwood J., Lowry S.,
RA Gordon L.A., Scott D., Xie G., Huang W., Hellsten U., Tran-Gyamfi M.,
RA She X., Prabhakar S., Aerts A., Altherr M., Bajorek E., Black S.,
RA Branscomb E., Caoile C., Challacombe J.F., Chan Y.M., Denys M.,
RA Detter J.C., Escobar J., Flowers D., Fotopulos D., Glavina T.,
RA Gomez M., Gonzales E., Goodstein D., Grigoriev I., Groza M.,
RA Hammon N., Hawkins T., Haydu L., Israni S., Jett J., Kadner K.,
RA Kimball H., Kobayashi A., Lopez F., Lou Y., Martinez D., Medina C.,
RA Morgan J., Nandkeshwar R., Noonan J.P., Pitluck S., Pollard M.,
RA Predki P., Priest J., Ramirez L., Retterer J., Rodriguez A.,
RA Rogers S., Salamov A., Salazar A., Thayer N., Tice H., Tsai M.,
RA Ustaszewska A., Vo N., Wheeler J., Wu K., Yang J., Dickson M.,
RA Cheng J.-F., Eichler E.E., Olsen A., Pennacchio L.A., Rokhsar D.S.,
RA Richardson P., Lucas S.M., Myers R.M., Rubin E.M.;
RT "The DNA sequence and comparative analysis of human chromosome 5.";
RL Nature 431:268-274(2004).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2), AND VARIANT
RP LEU-10.
RC TISSUE=Brain, and Testis;
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
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 3-559 (ISOFORM 1).
RC TISSUE=Mammary gland;
RA Yano K.;
RT "Nucleotide sequence of cDNA for human AMP-activated protein kinase
RT alpha-1.";
RL Submitted (JAN-1999) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 5-559 (ISOFORM 1).
RC TISSUE=Trachea;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 9-559 (ISOFORM 1).
RC TISSUE=Umbilical cord blood;
RX PubMed=11042152; DOI=10.1101/gr.140200;
RA Zhang Q.-H., Ye M., Wu X.-Y., Ren S.-X., Zhao M., Zhao C.-J., Fu G.,
RA Shen Y., Fan H.-Y., Lu G., Zhong M., Xu X.-R., Han Z.-G., Zhang J.-W.,
RA Tao J., Huang Q.-H., Zhou J., Hu G.-X., Gu J., Chen S.-J., Chen Z.;
RT "Cloning and functional analysis of cDNAs with open reading frames for
RT 300 previously undefined genes expressed in CD34+ hematopoietic
RT stem/progenitor cells.";
RL Genome Res. 10:1546-1560(2000).
RN [6]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 36-209 (ISOFORM 1).
RC TISSUE=Intestine;
RA Taboada E.N., Hickey D.A.;
RL Submitted (APR-1995) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 303-559 (ISOFORMS 1/2).
RC TISSUE=Liver;
RX PubMed=8557660; DOI=10.1074/jbc.271.2.611;
RA Stapleton D., Mitchelhill K.I., Gao G., Widmer J., Michell B.J.,
RA Teh T., House C.M., Fernandez C.S., Cox T., Witters L.A., Kemp B.E.;
RT "Mammalian AMP-activated protein kinase subfamily.";
RL J. Biol. Chem. 271:611-614(1996).
RN [8]
RP DOMAIN AIS.
RX PubMed=9857077; DOI=10.1074/jbc.273.52.35347;
RA Crute B.E., Seefeld K., Gamble J., Kemp B.E., Witters L.A.;
RT "Functional domains of the alpha1 catalytic subunit of the AMP-
RT activated protein kinase.";
RL J. Biol. Chem. 273:35347-35354(1998).
RN [9]
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 [10]
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
RT receptors.";
RL J. Biol. Chem. 276:38341-38344(2001).
RN [11]
RP ENZYME 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.,
RA Goodyear L.J., Moller D.E.;
RT "Role of AMP-activated protein kinase in mechanism of metformin
RT action.";
RL J. Clin. Invest. 108:1167-1174(2001).
RN [12]
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
RT kinase in polarized T84 cells.";
RL Am. J. Physiol. 284:C1297-C1308(2003).
RN [13]
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 [14]
RP PHOSPHORYLATION AT THR-183, AND ENZYME REGULATION.
RX PubMed=14976552; DOI=10.1038/sj.emboj.7600110;
RA Lizcano J.M., Goeransson O., Toth R., Deak M., Morrice N.A.,
RA Boudeau J., Hawley S.A., Udd L., Maekelae T.P., Hardie D.G.,
RA Alessi D.R.;
RT "LKB1 is a master kinase that activates 13 kinases of the AMPK
RT subfamily, including MARK/PAR-1.";
RL EMBO J. 23:833-843(2004).
RN [15]
RP PHOSPHORYLATION AT THR-183, AND ENZYME REGULATION.
RX PubMed=16054095; DOI=10.1016/j.cmet.2005.05.009;
RA Hawley S.A., Pan D.A., Mustard K.J., Ross L., Bain J., Edelman A.M.,
RA Frenguelli B.G., Hardie D.G.;
RT "Calmodulin-dependent protein kinase kinase-beta is an alternative
RT upstream kinase for AMP-activated protein kinase.";
RL Cell Metab. 2:9-19(2005).
RN [16]
RP PHOSPHORYLATION AT THR-183, AND ENZYME 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-
RT activated protein kinase kinases.";
RL J. Biol. Chem. 280:29060-29066(2005).
RN [17]
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.,
RA Birnbaum M.J., Thompson C.B.;
RT "AMP-activated protein kinase induces a p53-dependent metabolic
RT checkpoint.";
RL Mol. Cell 18:283-293(2005).
RN [18]
RP INTERACTION WITH FNIP1.
RX PubMed=17028174; DOI=10.1073/pnas.0603781103;
RA Baba M., Hong S.-B., Sharma N., Warren M.B., Nickerson M.L.,
RA Iwamatsu A., Esposito D., Gillette W.K., Hopkins R.F. III,
RA Hartley J.L., Furihata M., Oishi S., Zhen W., Burke T.R. Jr.,
RA Linehan W.M., Schmidt L.S., Zbar B.;
RT "Folliculin encoded by the BHD gene interacts with a binding protein,
RT FNIP1, and AMPK, and is involved in AMPK and mTOR signaling.";
RL Proc. Natl. Acad. Sci. U.S.A. 103:15552-15557(2006).
RN [19]
RP DOMAIN AIS, AND MUTAGENESIS OF VAL-307.
RX PubMed=17088252; DOI=10.1074/jbc.M605790200;
RA Pang T., Xiong B., Li J.Y., Qiu B.Y., Jin G.Z., Shen J.K., Li J.;
RT "Conserved alpha-helix acts as autoinhibitory sequence in AMP-
RT activated protein kinase alpha subunits.";
RL J. Biol. Chem. 282:495-506(2007).
RN [20]
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.,
RA Gygi S.P., 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 [21]
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
RT protein kinase.";
RL Nature 447:1017-1020(2007).
RN [22]
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.,
RA Schertzer J.D., 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 [23]
RP INTERACTION WITH FNIP2.
RX PubMed=18403135; DOI=10.1016/j.gene.2008.02.022;
RA Hasumi H., Baba M., Hong S.-B., Hasumi Y., Huang Y., Yao M.,
RA Valera V.A., Linehan W.M., Schmidt L.S.;
RT "Identification and characterization of a novel folliculin-interacting
RT protein FNIP2.";
RL Gene 415:60-67(2008).
RN [24]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-382, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18220336; DOI=10.1021/pr0705441;
RA Cantin G.T., Yi W., Lu B., Park S.K., Xu T., Lee J.-D.,
RA Yates J.R. III;
RT "Combining protein-based IMAC, peptide-based IMAC, and MudPIT for
RT efficient phosphoproteomic analysis.";
RL J. Proteome Res. 7:1346-1351(2008).
RN [25]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Platelet;
RX PubMed=18088087; DOI=10.1021/pr0704130;
RA Zahedi R.P., Lewandrowski U., Wiesner J., Wortelkamp S., Moebius J.,
RA Schuetz C., Walter U., Gambaryan S., Sickmann A.;
RT "Phosphoproteome of resting human platelets.";
RL J. Proteome Res. 7:526-534(2008).
RN [26]
RP FUNCTION IN PHOSPHORYLATION OF RPTOR.
RX PubMed=18439900; DOI=10.1016/j.molcel.2008.03.003;
RA Gwinn D.M., Shackelford D.B., Egan D.F., Mihaylova M.M., Mery A.,
RA Vasquez D.S., Turk B.E., Shaw R.J.;
RT "AMPK phosphorylation of raptor mediates a metabolic checkpoint.";
RL Mol. Cell 30:214-226(2008).
RN [27]
RP IDENTIFICATION BY 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
RT the kinome across the cell cycle.";
RL Mol. Cell 31:438-448(2008).
RN [28]
RP INTERACTION WITH FNIP2.
RX PubMed=18663353; DOI=10.1038/onc.2008.261;
RA Takagi Y., Kobayashi T., Shiono M., Wang L., Piao X., Sun G.,
RA Zhang D., Abe M., Hagiwara Y., Takahashi K., Hino O.;
RT "Interaction of folliculin (Birt-Hogg-Dube gene product) with a novel
RT Fnip1-like (FnipL/Fnip2) protein.";
RL Oncogene 27:5339-5347(2008).
RN [29]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-356; SER-486; THR-490
RP AND SER-496, AND MASS SPECTROMETRY.
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 [30]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-32 AND SER-467, AND MASS
RP SPECTROMETRY.
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 [31]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-382, AND MASS
RP SPECTROMETRY.
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [32]
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.,
RA Rutter G.A.;
RT "Cell-wide analysis of secretory granule dynamics in three dimensions
RT in living pancreatic beta-cells: evidence against a role for AMPK-
RT dependent phosphorylation of KLC1 at Ser517/Ser520 in glucose-
RT stimulated insulin granule movement.";
RL Biochem. Soc. Trans. 38:205-208(2010).
RN [33]
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.,
RA Inoki K., Guan K.L., Shen J., Person M.D., Kusewitt D., Mills G.B.,
RA Kastan M.B., Walker C.L.;
RT "ATM signals to TSC2 in the cytoplasm to regulate mTORC1 in response
RT to ROS.";
RL Proc. Natl. Acad. Sci. U.S.A. 107:4153-4158(2010).
RN [34]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [35]
RP PHOSPHORYLATION BY ULK1 AND ULK2.
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
RT regulatory feedback loop.";
RL Autophagy 7:696-706(2011).
RN [36]
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.,
RA Buerckstuemmer T., 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 [37]
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
RT connects energy sensing to mitophagy.";
RL Science 331:456-461(2011).
RN [38]
RP INTERACTION WITH PRKAB1 AND PRKAG1, AND ENZYME REGULATION.
RX PubMed=21680840; DOI=10.1126/science.1200094;
RA Oakhill J.S., Steel R., Chen Z.P., Scott J.W., Ling N., Tam S.,
RA Kemp B.E.;
RT "AMPK is a direct adenylate charge-regulated protein kinase.";
RL Science 332:1433-1435(2011).
RN [39]
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
RT signaling.";
RL Circ. Res. 100:328-341(2007).
RN [40]
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 [41]
RP DEPHOSPHORYLATION.
RX PubMed=23088624; DOI=10.1042/BJ20121201;
RA Chida T., Ando M., Matsuki T., Masu Y., Nagaura Y.,
RA Takano-Yamamoto T., Tamura S., Kobayashi T.;
RT "N-Myristoylation is essential for protein phosphatases PPM1A and
RT PPM1B to dephosphorylate their physiological substrates in cells.";
RL Biochem. J. 449:741-749(2013).
RN [42]
RP VARIANT [LARGE SCALE ANALYSIS] ARG-16.
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.,
RA Buckhaults P., Farrell C., Meeh P., Markowitz S.D., Willis J.,
RA Dawson D., Willson J.K.V., Gazdar A.F., Hartigan J., Wu L., Liu C.,
RA Parmigiani G., Park B.H., Bachman K.E., Papadopoulos N.,
RA Vogelstein B., Kinzler K.W., Velculescu V.E.;
RT "The consensus coding sequences of human breast and colorectal
RT cancers.";
RL Science 314:268-274(2006).
CC -!- FUNCTION: Catalytic subunit of AMP-activated protein kinase
CC (AMPK), an energy sensor protein kinase that plays a key role in
CC regulating cellular energy metabolism. In response to reduction of
CC intracellular ATP levels, AMPK activates energy-producing pathways
CC and inhibits energy-consuming processes: inhibits protein,
CC carbohydrate and lipid biosynthesis, as well as cell growth and
CC proliferation. AMPK acts via direct phosphorylation of metabolic
CC enzymes, and by longer-term effects via phosphorylation of
CC transcription regulators. Also acts as a regulator of cellular
CC polarity by remodeling the actin cytoskeleton; probably by
CC indirectly activating myosin. Regulates lipid synthesis by
CC phosphorylating and inactivating lipid metabolic enzymes such as
CC ACACA, ACACB, GYS1, HMGCR and LIPE; regulates fatty acid and
CC cholesterol synthesis by phosphorylating acetyl-CoA carboxylase
CC (ACACA and ACACB) and hormone-sensitive lipase (LIPE) enzymes,
CC respectively. Regulates insulin-signaling and glycolysis by
CC phosphorylating IRS1, PFKFB2 and PFKFB3. AMPK stimulates glucose
CC uptake in muscle by increasing the translocation of the glucose
CC transporter SLC2A4/GLUT4 to the plasma membrane, possibly by
CC mediating phosphorylation of TBC1D4/AS160. Regulates transcription
CC and chromatin structure by phosphorylating transcription
CC regulators involved in energy metabolism such as CRTC2/TORC2,
CC FOXO3, histone H2B, HDAC5, MEF2C, MLXIPL/ChREBP, EP300, HNF4A,
CC p53/TP53, SREBF1, SREBF2 and PPARGC1A. Acts as a key regulator of
CC glucose homeostasis in liver by phosphorylating CRTC2/TORC2,
CC leading to CRTC2/TORC2 sequestration in the cytoplasm. In response
CC 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
CC ATG1/ULK1: in response to nutrient limitation, negatively
CC regulates the mTORC1 complex by phosphorylating RPTOR component of
CC the mTORC1 complex and by phosphorylating and activating TSC2. In
CC response to nutrient limitation, promotes autophagy by
CC phosphorylating and activating ATG1/ULK1. AMPK also acts as a
CC regulator of circadian rhythm by mediating phosphorylation of
CC CRY1, leading to destabilize it. May regulate the Wnt signaling
CC pathway by phosphorylating CTNNB1, leading to stabilize it. Also
CC has tau-protein kinase activity: in response to amyloid beta A4
CC protein (APP) exposure, activated by CAMKK2, leading to
CC phosphorylation of MAPT/TAU; however the relevance of such data
CC remains unclear in vivo. Also phosphorylates CFTR, EEF2K, KLC1,
CC NOS3 and SLC12A1.
CC -!- CATALYTIC ACTIVITY: ATP + a protein = ADP + a phosphoprotein.
CC -!- CATALYTIC ACTIVITY: ATP + [tau protein] = ADP + [tau protein]
CC phosphate.
CC -!- CATALYTIC ACTIVITY: ATP + [hydroxymethylglutaryl-CoA reductase
CC (NADPH)] = ADP + [hydroxymethylglutaryl-CoA reductase (NADPH)]
CC phosphate.
CC -!- CATALYTIC ACTIVITY: ATP + [acetyl-CoA carboxylase] = ADP +
CC [acetyl-CoA carboxylase] phosphate.
CC -!- COFACTOR: Magnesium.
CC -!- ENZYME REGULATION: Activated by phosphorylation on Thr-183.
CC Binding of AMP to non-catalytic gamma subunit (PRKAG1, PRKAG2 or
CC PRKAG3) results in allosteric activation, inducing phosphorylation
CC on Thr-183. AMP-binding to gamma subunit also sustains activity by
CC preventing dephosphorylation of Thr-183. ADP also stimulates Thr-
CC 183 phosphorylation, without stimulating already phosphorylated
CC AMPK. ATP promotes dephosphorylation of Thr-183, rendering the
CC enzyme inactive. Under physiological conditions AMPK mainly exists
CC in its inactive form in complex with ATP, which is much more
CC abundant than AMP. AMPK is activated by antihyperglycemic drug
CC metformin, a drug prescribed to patients with type 2 diabetes: in
CC vivo, metformin seems to mainly inhibit liver gluconeogenesis.
CC However, metformin can be used to activate AMPK in muscle and
CC other cells in culture or ex vivo (PubMed:11602624). Selectively
CC inhibited by compound C (6-[4-(2-Piperidin-1-yl-ethoxy)-phenyl)]-
CC 3-pyridin-4-yl-pyyrazolo[1,5-a] pyrimidine. Activated by
CC resveratrol, a natural polyphenol present in red wine, and S17834,
CC a synthetic polyphenol.
CC -!- SUBUNIT: AMPK is a heterotrimer of an alpha catalytic subunit
CC (PRKAA1 or PRKAA2), a beta (PRKAB1 or PRKAB2) and a gamma non-
CC catalytic subunits (PRKAG1, PRKAG2 or PRKAG3). Interacts with
CC FNIP1 and FNIP2.
CC -!- INTERACTION:
CC P08238:HSP90AB1; NbExp=2; IntAct=EBI-1181405, EBI-352572;
CC Q9Y478:PRKAB1; NbExp=5; IntAct=EBI-1181405, EBI-719769;
CC O43741:PRKAB2; NbExp=6; IntAct=EBI-1181405, EBI-1053424;
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Nucleus. Note=In response to
CC stress, recruited by p53/TP53 to specific promoters.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q13131-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q13131-2; Sequence=VSP_035431;
CC -!- DOMAIN: The AIS (autoinhibitory sequence) region shows some
CC sequence similarity with the ubiquitin-associated domains and
CC represses kinase activity.
CC -!- PTM: Ubiquitinated (By similarity).
CC -!- PTM: Phosphorylated at Thr-183 by STK11/LKB1 in complex with
CC STE20-related adapter-alpha (STRADA) pseudo kinase and CAB39. Also
CC phosphorylated at Thr-183 by CAMKK2; triggered by a rise in
CC intracellular calcium ions, without detectable changes in the
CC AMP/ATP ratio. CAMKK1 can also phosphorylate Thr-183, but at a
CC much lower level. Dephosphorylated by protein phosphatase 2A and
CC 2C (PP2A and PP2C). Phosphorylated by ULK1 and ULK2; leading to
CC negatively regulate AMPK activity and suggesting the existence of
CC a regulatory feedback loop between ULK1, ULK2 and AMPK.
CC Dephosphorylated by PPM1A and PPM1B.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. CAMK
CC Ser/Thr protein kinase family. SNF1 subfamily.
CC -!- SIMILARITY: Contains 1 protein kinase domain.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAA64850.1; Type=Erroneous initiation; Note=Translation N-terminally extended;
CC Sequence=AAD43027.1; Type=Erroneous initiation; Note=Translation N-terminally extended;
CC Sequence=AAH37303.1; Type=Erroneous initiation; Note=Translation N-terminally extended;
CC Sequence=BAA36547.1; Type=Erroneous initiation; Note=Translation N-terminally extended;
CC Sequence=BAG35788.1; Type=Erroneous initiation; Note=Translation N-terminally extended;
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DR EMBL; AC008810; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC048980; AAH48980.1; -; mRNA.
DR EMBL; AB022017; BAA36547.1; ALT_INIT; mRNA.
DR EMBL; AK312947; BAG35788.1; ALT_INIT; mRNA.
DR EMBL; BC037303; AAH37303.1; ALT_INIT; mRNA.
DR EMBL; AF100763; AAD43027.1; ALT_INIT; mRNA.
DR EMBL; U22456; AAA64850.1; ALT_INIT; mRNA.
DR EMBL; Y12856; CAA73361.1; -; mRNA.
DR PIR; G01743; G01743.
DR RefSeq; NP_006242.5; NM_006251.5.
DR RefSeq; NP_996790.3; NM_206907.3.
DR UniGene; Hs.43322; -.
DR ProteinModelPortal; Q13131; -.
DR SMR; Q13131; 18-559.
DR DIP; DIP-39973N; -.
DR IntAct; Q13131; 62.
DR MINT; MINT-6771251; -.
DR STRING; 9606.ENSP00000346148; -.
DR BindingDB; Q13131; -.
DR ChEMBL; CHEMBL2096907; -.
DR DrugBank; DB00131; Adenosine monophosphate.
DR DrugBank; DB00171; Adenosine triphosphate.
DR DrugBank; DB00914; Phenformin.
DR GuidetoPHARMACOLOGY; 1541; -.
DR PhosphoSite; Q13131; -.
DR DMDM; 254763436; -.
DR PaxDb; Q13131; -.
DR PRIDE; Q13131; -.
DR DNASU; 5562; -.
DR Ensembl; ENST00000354209; ENSP00000346148; ENSG00000132356.
DR Ensembl; ENST00000397128; ENSP00000380317; ENSG00000132356.
DR GeneID; 5562; -.
DR KEGG; hsa:5562; -.
DR UCSC; uc003jmc.3; human.
DR CTD; 5562; -.
DR GeneCards; GC05M040759; -.
DR H-InvDB; HIX0004832; -.
DR HGNC; HGNC:9376; PRKAA1.
DR HPA; CAB005050; -.
DR MIM; 602739; gene.
DR neXtProt; NX_Q13131; -.
DR PharmGKB; PA33744; -.
DR eggNOG; COG0515; -.
DR HOGENOM; HOG000233016; -.
DR HOVERGEN; HBG050432; -.
DR KO; K07198; -.
DR OMA; MKRATIR; -.
DR OrthoDB; EOG7RRF6K; -.
DR BRENDA; 2.7.11.1; 2681.
DR Reactome; REACT_111102; Signal Transduction.
DR SignaLink; Q13131; -.
DR ChiTaRS; PRKAA1; human.
DR GeneWiki; Protein_kinase,_AMP-activated,_alpha_1; -.
DR GenomeRNAi; 5562; -.
DR NextBio; 21546; -.
DR PRO; PR:Q13131; -.
DR ArrayExpress; Q13131; -.
DR Bgee; Q13131; -.
DR CleanEx; HS_PRKAA1; -.
DR Genevestigator; Q13131; -.
DR GO; GO:0031588; C:AMP-activated protein kinase complex; ISS:UniProtKB.
DR GO; GO:0016324; C:apical plasma membrane; IEA:Ensembl.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005634; C:nucleus; ISS:UniProtKB.
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:0004691; F:cAMP-dependent protein kinase activity; NAS:UniProtKB.
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:0050321; F:tau-protein kinase activity; IEA:UniProtKB-EC.
DR GO; GO:0000187; P:activation of MAPK activity; NAS:UniProtKB.
DR GO; GO:0006914; P:autophagy; IEA:UniProtKB-KW.
DR GO; GO:0007050; P:cell cycle arrest; TAS:Reactome.
DR GO; GO:0071361; P:cellular response to ethanol; IEA:Ensembl.
DR GO; GO:0042149; P:cellular response to glucose starvation; ISS:UniProtKB.
DR GO; GO:0070301; P:cellular response to hydrogen peroxide; IEA:Ensembl.
DR GO; GO:0071456; P:cellular response to hypoxia; IEA:Ensembl.
DR GO; GO:0006695; P:cholesterol biosynthetic process; IEA:UniProtKB-KW.
DR GO; GO:0009631; P:cold acclimation; IEA:Ensembl.
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:0019395; P:fatty acid oxidation; IEA:Ensembl.
DR GO; GO:0042593; P:glucose homeostasis; ISS:UniProtKB.
DR GO; GO:0006006; P:glucose metabolic process; IEA:Ensembl.
DR GO; GO:0008286; P:insulin receptor signaling pathway; TAS:Reactome.
DR GO; GO:0008610; P:lipid biosynthetic process; ISS:UniProtKB.
DR GO; GO:0043066; P:negative regulation of apoptotic process; ISS:UniProtKB.
DR GO; GO:2001274; P:negative regulation of glucose import in response to insulin stimulus; IEA:Ensembl.
DR GO; GO:0046318; P:negative regulation of glucosylceramide biosynthetic process; NAS:UniProtKB.
DR GO; GO:0050995; P:negative regulation of lipid catabolic process; ISS:UniProtKB.
DR GO; GO:0032007; P:negative regulation of TOR signaling cascade; ISS:UniProtKB.
DR GO; GO:0010508; P:positive regulation of autophagy; ISS:UniProtKB.
DR GO; GO:0008284; P:positive regulation of cell proliferation; IEA:Ensembl.
DR GO; GO:0045542; P:positive regulation of cholesterol biosynthetic process; NAS:UniProtKB.
DR GO; GO:0010628; P:positive regulation of gene expression; IDA:UniProtKB.
DR GO; GO:0045821; P:positive regulation of glycolysis; ISS:UniProtKB.
DR GO; GO:0051291; P:protein heterooligomerization; IEA:Ensembl.
DR GO; GO:0042752; P:regulation of circadian rhythm; ISS:UniProtKB.
DR GO; GO:2000505; P:regulation of energy homeostasis; ISS:UniProtKB.
DR GO; GO:0006355; P:regulation of transcription, DNA-dependent; IEA:UniProtKB-KW.
DR GO; GO:0060627; P:regulation of vesicle-mediated transport; IEA:Ensembl.
DR GO; GO:0014823; P:response to activity; IEA:Ensembl.
DR GO; GO:0031000; P:response to caffeine; IEA:Ensembl.
DR GO; GO:0001666; P:response to hypoxia; NAS:UniProtKB.
DR GO; GO:0048511; P:rhythmic process; IEA:UniProtKB-KW.
DR GO; GO:0006351; P:transcription, DNA-dependent; IEA:UniProtKB-KW.
DR GO; GO:0016055; P:Wnt receptor signaling pathway; IEA:UniProtKB-KW.
DR InterPro; IPR028375; KA1/Ssp2_C.
DR InterPro; IPR011009; Kinase-like_dom.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR InterPro; IPR002290; Ser/Thr_dual-sp_kinase_dom.
DR InterPro; IPR008271; Ser/Thr_kinase_AS.
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 Alternative splicing; ATP-binding; Autophagy; Biological rhythms;
KW Cholesterol biosynthesis; Cholesterol metabolism; Chromatin regulator;
KW Complete proteome; Cytoplasm; Fatty acid biosynthesis;
KW Fatty acid metabolism; Kinase; Lipid biosynthesis; Lipid metabolism;
KW Magnesium; Metal-binding; Nucleotide-binding; Nucleus; Phosphoprotein;
KW Polymorphism; Reference proteome; Serine/threonine-protein kinase;
KW Steroid biosynthesis; Steroid metabolism; Sterol biosynthesis;
KW Sterol metabolism; Transcription; Transcription regulation;
KW Transferase; Ubl conjugation; Wnt signaling pathway.
FT CHAIN 1 559 5'-AMP-activated protein kinase catalytic
FT subunit alpha-1.
FT /FTId=PRO_0000085589.
FT DOMAIN 27 279 Protein kinase.
FT NP_BIND 33 41 ATP (By similarity).
FT REGION 302 381 AIS.
FT ACT_SITE 150 150 Proton acceptor (By similarity).
FT BINDING 56 56 ATP (By similarity).
FT MOD_RES 32 32 Phosphothreonine.
FT MOD_RES 183 183 Phosphothreonine; by LKB1 and CaMKK2 (By
FT similarity).
FT MOD_RES 269 269 Phosphothreonine (By similarity).
FT MOD_RES 356 356 Phosphoserine.
FT MOD_RES 360 360 Phosphoserine; by ULK1 (By similarity).
FT MOD_RES 368 368 Phosphothreonine; by ULK1 (By
FT similarity).
FT MOD_RES 382 382 Phosphothreonine.
FT MOD_RES 397 397 Phosphoserine; by ULK1 (Probable).
FT MOD_RES 467 467 Phosphoserine.
FT MOD_RES 486 486 Phosphoserine.
FT MOD_RES 488 488 Phosphothreonine; by ULK1 (Probable).
FT MOD_RES 490 490 Phosphothreonine.
FT MOD_RES 496 496 Phosphoserine.
FT VAR_SEQ 121 121 R -> RKSDVPGVVKTGSTKE (in isoform 2).
FT /FTId=VSP_035431.
FT VARIANT 10 10 M -> L (in dbSNP:rs17855679).
FT /FTId=VAR_058401.
FT VARIANT 16 16 Q -> R (in a breast cancer sample;
FT somatic mutation).
FT /FTId=VAR_035622.
FT MUTAGEN 307 307 V->G,Q: Activates the kinase activity.
FT CONFLICT 5 5 S -> C (in Ref. 4; BAG35788).
FT CONFLICT 9 9 K -> S (in Ref. 5; AAD43027).
FT CONFLICT 37 37 T -> A (in Ref. 6; AAA64850).
FT CONFLICT 202 202 A -> V (in Ref. 6; AAA64850).
FT CONFLICT 208 208 I -> L (in Ref. 6; AAA64850).
FT CONFLICT 269 269 T -> S (in Ref. 3; BAA36547).
SQ SEQUENCE 559 AA; 64009 MW; ABAE71FBF912947A CRC64;
MRRLSSWRKM ATAEKQKHDG RVKIGHYILG DTLGVGTFGK VKVGKHELTG HKVAVKILNR
QKIRSLDVVG KIRREIQNLK LFRHPHIIKL YQVISTPSDI FMVMEYVSGG ELFDYICKNG
RLDEKESRRL FQQILSGVDY CHRHMVVHRD LKPENVLLDA HMNAKIADFG LSNMMSDGEF
LRTSCGSPNY AAPEVISGRL YAGPEVDIWS SGVILYALLC GTLPFDDDHV PTLFKKICDG
IFYTPQYLNP SVISLLKHML QVDPMKRATI KDIREHEWFK QDLPKYLFPE DPSYSSTMID
DEALKEVCEK FECSEEEVLS CLYNRNHQDP LAVAYHLIID NRRIMNEAKD FYLATSPPDS
FLDDHHLTRP HPERVPFLVA ETPRARHTLD ELNPQKSKHQ GVRKAKWHLG IRSQSRPNDI
MAEVCRAIKQ LDYEWKVVNP YYLRVRRKNP VTSTYSKMSL QLYQVDSRTY LLDFRSIDDE
ITEAKSGTAT PQRSGSVSNY RSCQRSDSDA EAQGKSSEVS LTSSVTSLDS SPVDLTPRPG
SHTIEFFEMC ANLIKILAQ
//

MIM 602739
*RECORD*
*FIELD* NO
602739
*FIELD* TI
*602739 PROTEIN KINASE, AMP-ACTIVATED, CATALYTIC, ALPHA-1; PRKAA1
;;AMP-ACTIVATED PROTEIN KINASE, CATALYTIC, ALPHA-1;;
read moreAMPK-ALPHA-1
*FIELD* TX
The mammalian 5-prime-AMP-activated protein kinase (AMPK) appears to
play a role in protecting cells from stresses that cause ATP depletion
by switching off ATP-consuming biosynthetic pathways. AMPK is a
heterotrimeric protein composed of 1 alpha subunit, 1 beta subunit
(e.g., PRKAB1; 602740), and 1 gamma subunit (e.g., PRKAG1; 602742). The
catalytic alpha subunit requires phosphorylation for full activity. It
is related to the S. cerevisiae Snf1 protein kinase, which is involved
in the response to nutritional stress. The noncatalytic beta and gamma
subunits are related to yeast proteins that interact with Snf1: the beta
subunit to the Sip1/Sip2/Gal83 family of transcription regulators, and
the gamma subunit to Snf4, which is thought to be an activator of Snf1.

CLONING

Stapleton et al. (1996) reported the sequences of partial human liver
cDNAs encoding AMPK-alpha-1.

Stapleton et al. (1996) cloned rat hypothalamus cDNAs encoding
Ampk-alpha-1. By Northern blot analysis, they detected low levels of a
6-kb Ampk-alpha-1 mRNA in all rat tissues examined except testis, where
a low level of a 2.4-kb transcript was observed. The predicted 548-amino
acid protein has a molecular mass of approximately 63 kD by SDS-PAGE.
Rat Ampk-alpha-1 and Ampk-alpha-2 (600497) have 90% amino acid sequence
identity within their catalytic cores but only 61% in their C-terminal
tails.

MAPPING

By fluorescence in situ hybridization, Stapleton et al. (1997) mapped
the human AMPK-alpha-1 gene to 5p12.

GENE FUNCTION

Adiponectin (605441) is a hormone secreted by adipocytes that regulates
energy homeostasis and glucose and lipid metabolism. Yamauchi et al.
(2002) demonstrated that phosphorylation and activation of AMPK are
stimulated with globular and full-length adiponectin in skeletal muscle
and only with full-length adiponectin in the liver. In parallel with its
activation of AMPK, adiponectin stimulates phosphorylation of acetyl
coenzyme A carboxylase (ACC1; 200350), fatty acid oxidation, glucose
uptake and lactate production in myocytes, phosphorylation of ACC and
reduction of molecules involved in gluconeogenesis in the liver, and
reduction of glucose levels in vivo. Blocking AMPK activation by a
dominant-negative mutant inhibits each of these effects, indicating that
stimulation of glucose utilization and fatty acid oxidation by
adiponectin occurs through activation of AMPK. Yamauchi et al. (2002)
concluded that their data provided a novel paradigm, that an
adipocyte-derived antidiabetic hormone, adiponectin, activates AMPK,
thereby directly regulating glucose metabolism and insulin sensitivity
in vitro and in vivo.

Minokoshi et al. (2004) investigated the potential role of AMP-activated
protein kinase (AMPK) in the hypothalamus in the regulation of food
intake. Minokoshi et al. (2004) reported that AMPK activity is inhibited
in arcuate and paraventricular hypothalamus by the anorexigenic hormone
leptin (164160), and in multiple hypothalamic regions by insulin
(176730), high glucose, and refeeding. A melanocortin receptor (see
155555) agonist, a potent anorexigen, decreased AMPK activity in
paraventricular hypothalamus, whereas agouti-related protein (602311),
an orexigen, increased AMPK activity. Melanocortin receptor signaling is
required for leptin and refeeding effects of AMPK in the paraventricular
hypothalamus. Dominant-negative AMPK expression in the hypothalamus was
sufficient to reduce food intake and body weight, whereas constitutively
active AMPK increased both. Alterations of hypothalamic AMPK activity
augmented changes in arcuate neuropeptide expression induced by fasting
and feeding. Furthermore, inhibition of hypothalamic AMPK is necessary
for leptin's effects on food intake and body weight, as constitutively
active AMPK blocks these effects. Thus, Minokoshi et al. (2004)
concluded that hypothalamic AMPK plays a critical role in hormonal and
nutrient-derived anorexigenic and orexigenic signals and in energy
balance.

Baba et al. (2006) showed that FNIP1 (610594) interacted with the alpha,
beta, and gamma subunits of AMPK. FNIP1 was phosphorylated by AMPK, and
its phosphorylation was inhibited in a dose-dependent manner by an AMPK
inhibitor, resulting in reduced FNIP1 expression. FLCN (607273)
phosphorylation was diminished by rapamycin and amino acid starvation
and facilitated by FNIP1 overexpression, suggesting that FLCN
phosphorylation may be regulated by mTOR (FRAP1; 601231) and AMPK
signaling. Baba et al. (2006) concluded that FLCN and FNIP1 may be
involved in energy and/or nutrient sensing through the AMPK and mTOR
signaling pathways.

Miller et al. (2008) showed that macrophage migration inhibitory factor
(MIF; 153620), an upstream regulator of inflammation, is released in the
ischemic heart, where it stimulates AMPK activation through CD74
(142790), promotes glucose uptake, and protects the heart during
ischemia-reperfusion injury. Germline deletion of the Mif gene impairs
ischemic AMPK signaling in the mouse heart. Human fibroblasts with a
low-activity MIF promoter polymorphism have diminished MIF release and
AMPK activation during hypoxia. Thus, MIF modulates the activation of
the cardioprotective AMPK pathway during ischemia, functionally linking
inflammation and metabolism in the heart. Miller et al. (2008)
anticipated that genetic variation in MIF expression may influence the
response of the human heart to ischemia by the AMPK pathway, and that
diagnostic MIF genotyping might predict risk in patients with coronary
artery disease.

Canto et al. (2009) demonstrated that AMPK controls the expression of
genes involved in energy metabolism in mouse skeletal muscle by acting
in coordination with another metabolic sensor, the NAD+-dependent type
III deacetylase SIRT1 (604479). AMPK enhances SIRT1 activity by
increasing cellular NAD+ levels, resulting in the deacetylation and
modulation of the activity of downstream SIRT1 targets that include the
PPAR-gamma coactivator 1-alpha (604517) and the FOXO1A (136533) and
FOXO3A (602681) transcription factors. Canto et al. (2009) concluded
that the AMPK-induced SIRT1-mediated deacetylation of these targets
explains many of the convergent biologic effects of AMPK and SIRT1 on
energy metabolism.

Studying mouse fibroblasts, Lamia et al. (2009) demonstrated that the
nutrient-responsive adenosine monophosphate-activated protein kinase
(AMPK) phosphorylates and destabilizes the clock component
cryptochrome-1 (CRY1; 601933). In mouse livers, AMPK activity and
nuclear localization were rhythmic and inversely correlated with CRY1
nuclear protein abundance. Stimulation of AMPK destabilized
cryptochromes and altered circadian rhythms, and mice in which the AMPK
pathway was genetically disrupted showed alterations in peripheral
clocks. Thus, Lamia et al. (2009) concluded that phosphorylation by AMPK
enables cryptochrome to transduce nutrient signals to circadian clocks
in mammalian peripheral organs.

Bungard et al. (2010) found that AMPK activates transcription through
direct association with chromatin and phosphorylation of histone H2B
(see 609904) at ser36. AMPK recruitment and H2B ser36 phosphorylation
colocalized within genes activated by AMPK-dependent pathways, both in
promoters and in transcribed regions. Ectopic expression of H2B in which
ser36 was substituted by alanine reduced transcription and RNA
polymerase II (see 180660) association to AMPK-dependent genes, and
lowered cell survival in response to stress. Bungard et al. (2010)
concluded that their results placed AMPK-dependent H2B serine-36
phosphorylation in a direct transcriptional and chromatin regulatory
pathway leading to cellular adaptation to stress.

AMPK is an alpha-beta-gamma heterotrimer activated by decreasing
concentrations of adenosine triphosphate (ATP) and increasing AMP
concentrations (summary by Oakhill et al., 2011). AMPK activation
depends on phosphorylation of the alpha catalytic subunit on thr172 by
kinases LKB1 (602216) or CaMKK-beta (CAMKK2; 615002), and this is
promoted by AMP binding to the gamma subunit (602742). AMP sustains
activity by inhibiting dephosphorylation of alpha-thr172, whereas ATP
promotes dephosphorylation. Oakhill et al. (2011) found that adenosine
diphosphate (ADP), like AMP, bound to gamma sites 1 and 3 and stimulated
alpha-thr172 phosphorylation. However, in contrast to AMP, ADP did not
directly activate phosphorylated AMPK. In this way, both ADP/ATP and
AMP/ATP ratios contribute to AMPK regulation.

Salicylate, the active component of willow bark, has been in medicinal
use since ancient times and has more recently been replaced by synthetic
derivatives such as aspirin and salsalate. Using concentrations of
salicylate reached in plasma after administration of high-dose aspirin
or salsalate, Hawley et al. (2012) showed that salicylate activated
AMPK. Salicylate bound AMPK at the same site as a synthetic activator to
cause allosteric activation and inhibition of dephosphorylation at the
activating site, thr172. In mice lacking Ampk, the effects of salicylate
to increase fat utilization and to lower plasma fatty acid were lost.
Hawley et al. (2012) proposed that AMPK activation explains some
beneficial effects of salsalate and aspirin.

Jeon et al. (2012) demonstrated that AMPK activation, during energy
stress, prolongs cell survival by redox regulation. Under these
conditions, NADPH generation by the pentose phosphate pathway is
impaired, but AMPK induces alternative routes to maintain NADPH and
inhibit cell death. The inhibition of the acetyl-CoA carboxylases ACC1
(200350) and ACC2 (601557) by AMPK maintains NADPH levels by decreasing
NADPH consumption in fatty acid synthesis and increasing NADPH
generation by means of fatty acid oxidation. Knockdown of either ACC1 or
ACC2 compensates for AMPK activation and facilitates
anchorage-independent growth and solid tumor formation in vivo, whereas
the activation of ACC1 or ACC2 attenuates these processes. Thus AMPK, in
addition to its function in ATP homeostasis, has a key function in NADPH
maintenance, which is critical for cancer cell survival under energy
stress conditions, such as glucose limitations, anchorage-independent
growth, and solid tumor formation in vivo.

BIOCHEMICAL FEATURES

- Crystal Structure

Xiao et al. (2007) reported the crystal structure of the regulatory
fragment of mammalian AMPK in complexes with AMP and ATP. The phosphate
groups of AMP/ATP lie in a groove on the surface of the gamma domain,
which is lined with basic residues, many of which are associated with
disease-causing mutations. Structural and solution studies revealed that
2 sites on the gamma domain bind either AMP or magnesium ATP, whereas a
third site contains a tightly bound AMP that does not exchange. Xiao et
al. (2007) stated that their binding studies indicated that under
physiologic conditions AMPK mainly exists in its inactive form in
complex with magnesium ATP, which is much more abundant than AMP. Their
modeling studies suggested how changes in the concentration of AMP
enhance AMPK activity levels. The structure also suggested a mechanism
for propagating AMP/ATP signaling whereby a phosphorylated residue from
the alpha and/or beta subunits binds to the gamma subunit in the
presence of AMP but not when ATP is bound.

Xiao et al. (2011) showed that ADP binding to just 1 of the 2
exchangeable AXP (AMP/ADP/ATP) binding sites on the regulatory domain of
AMPK protects the enzyme from dephosphorylation, although it does not
lead to allosteric activation. Their studies showed that active
mammalian AMPK displays significantly tighter binding to ADP than to
Mg-ATP, explaining how the enzyme is regulated under physiologic
conditions where the concentration of Mg-ATP is higher than that of ADP
and much higher than that of AMP. Xiao et al. (2011) determined the
crystal structure of an active AMPK complex. The structure showed how
the activation loop of the kinase domain is stabilized by the regulatory
domain and how the kinase linker region interacts with the regulatory
nucleotide-binding site that mediates protection against
dephosphorylation. From their biochemical and structural data, Xiao et
al. (2011) developed a model for how the energy status of a cell
regulates AMPK activity.

HISTORY

Lin et al. (2012) reported that acetylation and deacetylation of the
catalytic subunit of AMPK, PRKAA1, a critical cellular energy-sensing
protein kinase complex, is controlled by the opposing catalytic
activities of HDAC1 (601241) and p300 (602700). Deacetylation of AMPK
enhanced physical interaction with the upstream kinase LKB1 (602216),
leading to AMPK phosphorylation and activation, and resulting in lipid
breakdown in human liver cells. The authors later found that the Methods
section in their article was inaccurate. Because they could not
reproduce all of their results, they retracted the article.

*FIELD* RF
1. Baba, M.; Hong, S.-B.; Sharma, N.; Warren, M. B.; Nickerson, M.
L.; Iwamatsu, A.; Esposito, D.; Gillette, W. K.; Hopkins, R. F., III;
Hartley, J. L.; Furihata, M.; Oishi, S.; Zhen, W.; Burke, T. R., Jr.;
Linehan, W. M.; Schmidt, L. S.; Zbar, B.: Folliculin encoded by the
BHD gene interacts with a binding protein, FNIP1, and AMPK, and is
involved in AMPK and mTOR signaling. Proc. Nat. Acad. Sci. 103:
15552-15557, 2006.

2. Bungard, D.; Fuerth, B. J.; Zeng, P.-Y.; Faubert, B.; Maas, N.
L.; Viollet, B.; Carling, D.; Thompson, C. B.; Jones, R. G.; Berger,
S. L.: Signaling kinase AMPK activates stress-promoted transcription
via histone H2B phosphorylation. Science 329: 1201-1205, 2010.

3. Canto, C.; Gerhart-Hines, Z.; Feige, J. N.; Lagouge, M.; Noriega,
L.; Milne, J. C.; Elliott, P. J.; Puigserver, P.; Auwerx, J.: AMPK
regulates energy expenditure by modulating NAD+ metabolism and SIRT1
activity. Nature 458: 1056-1060, 2009.

4. Hawley, S. A.; Fullerton, M. D.; Ross, F. A.; Schertzer, J. D.;
Chevtzoff, C.; Walker, K. J.; Peggie, M. W.; Zibrova, D.; Green, K.
A.; Mustard, K. J.; Kemp, B. E.; Sakamoto, K.; Steinberg, G. R.; Hardie,
D. G.: The ancient drug salicylate directly activates AMP-activated
protein kinase. Science 336: 918-922, 2012.

5. Jeon, S.-M.; Chandel, N. S.; Hay, N.: AMPK regulates NADPH homeostasis
to promote tumour cell survival during energy stress. Nature 485:
661-665, 2012.

6. Lamia, K. A.; Sachdeva, U. M.; DiTacchio, L.; Williams, E. C.;
Alvarez, J. G.; Egan, D. F.; Vasquez, D. S.; Juguilon, H.; Panda,
S.; Shaw, R. J.; Thompson, C. B.; Evans, R. M.: AMPK regulates the
circadian clock by cryptochrome phosphorylation and degradation. Science 326:
437-440, 2009.

7. Lin, Y.; Kiihl, S.; Suhail, Y.; Liu, S.-Y.; Chou, Y.; Kuang, Z.;
Lu, J.; Khor, C. N.; Lin, C.-L.; Bader, J. S.; Irizarry, R.; Boeke,
J. D.: Functional dissection of lysine deacetylases reveals that
HDAC1 and p300 regulate AMPK. Nature 482: 251-255, 2012. Note: Retraction:
Nature 503: 146 only, 2013.

8. Miller, E. J.; Li, J.; Leng, L.; McDonald, C.; Atsumi, T.; Bucala,
R.; Young, L. H.: Macrophage migration inhibitory factor stimulates
AMP-activated protein kinase in the ischaemic heart. Nature 451:
578-582, 2008.

9. Minokoshi, Y.; Alquier, T.; Furukawa, N.; Kim, Y.-B.; Lee, A.;
Xue, B.; Mu, J.; Foufelle, F.; Ferre, P.; Birnbaum, M. J.; Stuck,
B. J.; Kahn, B. B.: AMP-kinase regulates food intake by responding
to hormonal and nutrient signals in the hypothalamus. Nature 428:
569-574, 2004.

10. Oakhill, J. S.; Steel, R.; Chen, Z.-P.; Scott, J. W.; Ling, N.;
Tam, S.; Kemp, B. E.: AMPK is a direct adenylate charge-regulated
protein kinase. Science 332: 1433-1435, 2011.

11. Stapleton, D.; Mitchelhill, K. I.; Gao, G.; Widmer, J.; Michell,
B. J.; Teh, T.; House, C. M.; Fernandez, C. S.; Cox, T.; Witters,
L. A.; Kemp, B. E.: Mammalian AMP-activated protein kinase subfamily. J.
Biol. Chem. 271: 611-614, 1996.

12. Stapleton, D.; Woollatt, E.; Mitchelhill, K. I.; Nicholl, J. K.;
Fernandez, C. S.; Michell, B. J.; Witters, L. A.; Power, D. A.; Sutherland,
G. R.; Kemp, B. E.: AMP-activated protein kinase isoenzyme family:
subunit structure and chromosomal location. FEBS Lett. 409: 452-456,
1997.

13. Xiao, B.; Heath, R.; Saiu, P.; Leiper, F. C.; Leone, P.; Jing,
C.; Walker, P. A.; Haire, L.; Eccleston, J. F.; Davis, C. T.; Martin,
S. R.; Carling, D.; Gamblin, S. J.: Structural basis for AMP binding
to mammalian AMP-activated protein kinase. Nature 449: 496-500,
2007.

14. Xiao, B.; Sanders, M. J.; Underwood, E.; Heath, R.; Mayer, F.
V.; Carmena, D.; Jing, C.; Walker, P. A.; Eccleston, J. F.; Haire,
L. F.; Saiu, P.; Howell, S. A.; Aasland, R.; Martin, S. R.; Carling,
D.; Gamblin, S. J.: Structure of mammalian AMPK and its regulation
by ADP. Nature 472: 230-233, 2011.

15. Yamauchi, T.; Kamon, J.; Minokoshi, Y.; Ito, Y.; Waki, H.; Uchida,
S.; Yamashita, S.; Noda, M.; Kita, S.; Ueki, K.; Eto, K.; Akanuma,
Y.; Froguel, P.; Foufelle, F.; Ferre, P.; Carling, D.; Nagai, R.;
Kimura, S.; Kahn, B. B.; Kadowaki, T.: Adiponectin stimulates glucose
utilization and fatty-acid oxidation by activating AMP-activated protein
kinase. Nature Med. 8: 1288-1295, 2002.

*FIELD* CN
Ada Hamosh - updated: 7/19/2012
Paul J. Converse - updated: 6/8/2012
Ada Hamosh - updated: 3/7/2012
Ada Hamosh - updated: 7/1/2011
Ada Hamosh - updated: 6/7/2011
Ada Hamosh - updated: 10/28/2010
Ada Hamosh - updated: 11/10/2009
Ada Hamosh - updated: 5/11/2009
Ada Hamosh - updated: 4/14/2008
Ada Hamosh - updated: 10/11/2007
Dorothy S. Reilly - updated: 11/27/2006
Ada Hamosh - updated: 4/7/2004
Ada Hamosh - updated: 11/15/2002

*FIELD* CD
Rebekah S. Rasooly: 6/22/1998

*FIELD* ED
carol: 11/07/2013
mgross: 1/29/2013
carol: 12/20/2012
alopez: 7/23/2012
terry: 7/19/2012
mgross: 6/14/2012
terry: 6/8/2012
alopez: 4/16/2012
alopez: 3/12/2012
terry: 3/7/2012
alopez: 7/7/2011
terry: 7/1/2011
alopez: 6/9/2011
terry: 6/7/2011
alopez: 10/28/2010
alopez: 11/10/2009
terry: 11/10/2009
alopez: 5/14/2009
terry: 5/11/2009
wwang: 6/3/2008
terry: 5/30/2008
alopez: 4/14/2008
alopez: 10/16/2007
terry: 10/11/2007
wwang: 11/27/2006
alopez: 4/8/2004
terry: 4/7/2004
alopez: 11/18/2002
terry: 11/15/2002
dkim: 9/22/1998
psherman: 6/24/1998