AAPK2_MOUSE
ID AAPK2_MOUSE Reviewed; 552 AA.
AC Q8BRK8; B1ASQ8; Q3UYM4;
DT 28-NOV-2006, integrated into UniProtKB/Swiss-Prot.
DT 27-JUL-2011, sequence version 3.
DT 03-AUG-2022, entry version 164.
DE RecName: Full=5'-AMP-activated protein kinase catalytic subunit alpha-2;
DE Short=AMPK subunit alpha-2;
DE EC=2.7.11.1 {ECO:0000250|UniProtKB:Q09137};
DE AltName: Full=Acetyl-CoA carboxylase kinase;
DE Short=ACACA kinase;
DE EC=2.7.11.27 {ECO:0000250|UniProtKB:Q09137};
DE AltName: Full=Hydroxymethylglutaryl-CoA reductase kinase;
DE Short=HMGCR kinase;
DE EC=2.7.11.31 {ECO:0000250|UniProtKB:Q09137};
GN Name=Prkaa2 {ECO:0000312|MGI:MGI:1336173};
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=C57BL/6J;
RX PubMed=19468303; DOI=10.1371/journal.pbio.1000112;
RA Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X.,
RA Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y.,
RA Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S.,
RA Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R.,
RA Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K.,
RA Eichler E.E., Ponting C.P.;
RT "Lineage-specific biology revealed by a finished genome assembly of the
RT mouse.";
RL PLoS Biol. 7:E1000112-E1000112(2009).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain;
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 [3] {ECO:0000305, ECO:0000312|EMBL:BAC31746.1}
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 15-552.
RC STRAIN=C57BL/6J {ECO:0000312|EMBL:BAC31746.1};
RC TISSUE=Brain cortex {ECO:0000312|EMBL:BAC31746.1}, and
RC Medulla oblongata {ECO:0000312|EMBL:BAE22188.1};
RX PubMed=16141072; DOI=10.1126/science.1112014;
RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N.,
RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K.,
RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.,
RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R.,
RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T.,
RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A.,
RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B.,
RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M.,
RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S.,
RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E.,
RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D.,
RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M.,
RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H.,
RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V.,
RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S.,
RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H.,
RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N.,
RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F.,
RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G.,
RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z.,
RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C.,
RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y.,
RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S.,
RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K.,
RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R.,
RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H.,
RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M.,
RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C.,
RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S.,
RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K.,
RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M.,
RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C.,
RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A.,
RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.;
RT "The transcriptional landscape of the mammalian genome.";
RL Science 309:1559-1563(2005).
RN [4] {ECO:0000305}
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=15331533; DOI=10.2337/diabetes.53.9.2242;
RA Villena J.A., Viollet B., Andreelli F., Kahn A., Vaulont S., Sul H.S.;
RT "Induced adiposity and adipocyte hypertrophy in mice lacking the AMP-
RT activated protein kinase-alpha2 subunit.";
RL Diabetes 53:2242-2249(2004).
RN [5]
RP FUNCTION IN PHOSPHORYLATION OF GYS1.
RX PubMed=15561936; DOI=10.2337/diabetes.53.12.3074;
RA Jorgensen S.B., Nielsen J.N., Birk J.B., Olsen G.S., Viollet B.,
RA Andreelli F., Schjerling P., Vaulont S., Hardie D.G., Hansen B.F.,
RA Richter E.A., Wojtaszewski J.F.;
RT "The alpha2-5'AMP-activated protein kinase is a site 2 glycogen synthase
RT kinase in skeletal muscle and is responsive to glucose loading.";
RL Diabetes 53:3074-3081(2004).
RN [6]
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 [7]
RP FUNCTION IN PHOSPHORYLATION OF CRTC2.
RX PubMed=16148943; DOI=10.1038/nature03967;
RA Koo S.-H., Flechner L., Qi L., Zhang X., Screaton R.A., Jeffries S.,
RA Hedrick S., Xu W., Boussouar F., Brindle P., Takemori H., Montminy M.;
RT "The CREB coactivator TORC2 is a key regulator of fasting glucose
RT metabolism.";
RL Nature 437:1109-1111(2005).
RN [8]
RP FUNCTION IN PHOSPHORYLATION OF CRTC2, AND PHOSPHORYLATION AT THR-172.
RX PubMed=16308421; DOI=10.1126/science.1120781;
RA Shaw R.J., Lamia K.A., Vasquez D., Koo S.-H., Bardeesy N., Depinho R.A.,
RA Montminy M., Cantley L.C.;
RT "The kinase LKB1 mediates glucose homeostasis in liver and therapeutic
RT effects of metformin.";
RL Science 310:1642-1646(2005).
RN [9]
RP FUNCTION IN PHOSPHORYLATION OF TBC1D4.
RX PubMed=16804075; DOI=10.2337/db06-0175;
RA Treebak J.T., Glund S., Deshmukh A., Klein D.K., Long Y.C., Jensen T.E.,
RA Jorgensen S.B., Viollet B., Andersson L., Neumann D., Wallimann T.,
RA Richter E.A., Chibalin A.V., Zierath J.R., Wojtaszewski J.F.;
RT "AMPK-mediated AS160 phosphorylation in skeletal muscle is dependent on
RT AMPK catalytic and regulatory subunits.";
RL Diabetes 55:2051-2058(2006).
RN [10]
RP FUNCTION IN PHOSPHORYLATION OF TBC1D4.
RX PubMed=16804077; DOI=10.2337/db06-0150;
RA Kramer H.F., Witczak C.A., Fujii N., Jessen N., Taylor E.B., Arnolds D.E.,
RA Sakamoto K., Hirshman M.F., Goodyear L.J.;
RT "Distinct signals regulate AS160 phosphorylation in response to insulin,
RT AICAR, and contraction in mouse skeletal muscle.";
RL Diabetes 55:2067-2076(2006).
RN [11]
RP FUNCTION IN PHOSPHORYLATION OF PPARGC1A.
RX PubMed=17609368; DOI=10.1073/pnas.0705070104;
RA Jager S., Handschin C., St-Pierre J., Spiegelman B.M.;
RT "AMP-activated protein kinase (AMPK) action in skeletal muscle via direct
RT phosphorylation of PGC-1alpha.";
RL Proc. Natl. Acad. Sci. U.S.A. 104:12017-12022(2007).
RN [12]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-377, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=17242355; DOI=10.1073/pnas.0609836104;
RA Villen J., Beausoleil S.A., Gerber S.A., Gygi S.P.;
RT "Large-scale phosphorylation analysis of mouse liver.";
RL Proc. Natl. Acad. Sci. U.S.A. 104:1488-1493(2007).
RN [13]
RP UBIQUITINATION.
RX PubMed=18254724; DOI=10.1042/bj20080067;
RA Al-Hakim A.K., Zagorska A., Chapman L., Deak M., Peggie M., Alessi D.R.;
RT "Control of AMPK-related kinases by USP9X and atypical Lys(29)/Lys(33)-
RT linked polyubiquitin chains.";
RL Biochem. J. 411:249-260(2008).
RN [14]
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 [15]
RP FUNCTION IN PHOSPHORYLATION OF CRY1.
RX PubMed=19833968; DOI=10.1126/science.1172156;
RA Lamia K.A., Sachdeva U.M., DiTacchio L., Williams E.C., Alvarez J.G.,
RA Egan D.F., Vasquez D.S., Juguilon H., Panda S., Shaw R.J., Thompson C.B.,
RA Evans R.M.;
RT "AMPK regulates the circadian clock by cryptochrome phosphorylation and
RT degradation.";
RL Science 326:437-440(2009).
RN [16]
RP FUNCTION IN PHOSPHORYLATION OF CTNNB1.
RX PubMed=20361929; DOI=10.1016/j.bbrc.2010.03.161;
RA Zhao J., Yue W., Zhu M.J., Sreejayan N., Du M.;
RT "AMP-activated protein kinase (AMPK) cross-talks with canonical Wnt
RT signaling via phosphorylation of beta-catenin at Ser 552.";
RL Biochem. Biophys. Res. Commun. 395:146-151(2010).
RN [17]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-377, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Brain, Brown adipose tissue, Heart, Kidney, Liver, and Pancreas;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
RN [18]
RP FUNCTION IN PHOSPHORYLATION OF H2B, AND MUTAGENESIS OF ASP-157.
RX PubMed=20647423; DOI=10.1126/science.1191241;
RA Bungard D., Fuerth B.J., Zeng P.Y., Faubert B., Maas N.L., Viollet B.,
RA Carling D., Thompson C.B., Jones R.G., Berger S.L.;
RT "Signaling kinase AMPK activates stress-promoted transcription via histone
RT H2B phosphorylation.";
RL Science 329:1201-1205(2010).
RN [19]
RP FUNCTION IN PHOSPHORYLATION OF HDAC5, AND MUTAGENESIS OF LYS-45.
RX PubMed=21454484; DOI=10.1074/jbc.m110.199372;
RA Zhao J.X., Yue W.F., Zhu M.J., Du M.;
RT "AMP-activated protein kinase regulates beta-catenin transcription via
RT histone deacetylase 5.";
RL J. Biol. Chem. 286:16426-16434(2011).
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 FUNCTION IN PHOSPHORYLATION OF SREBF1 AND SREBF2, AND ACTIVITY REGULATION.
RX PubMed=21459323; DOI=10.1016/j.cmet.2011.03.009;
RA Li Y., Xu S., Mihaylova M.M., Zheng B., Hou X., Jiang B., Park O., Luo Z.,
RA Lefai E., Shyy J.Y., Gao B., Wierzbicki M., Verbeuren T.J., Shaw R.J.,
RA Cohen R.A., Zang M.;
RT "AMPK phosphorylates and inhibits SREBP activity to attenuate hepatic
RT steatosis and atherosclerosis in diet-induced insulin-resistant mice.";
RL Cell Metab. 13:376-388(2011).
RN [22]
RP FUNCTION IN PHOSPHORYLATION OF ULK1.
RX PubMed=21258367; DOI=10.1038/ncb2152;
RA Kim J., Kundu M., Viollet B., Guan K.L.;
RT "AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1.";
RL Nat. Cell Biol. 13:132-141(2011).
RN [23]
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 [24]
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 [25]
RP FUNCTION, PHOSPHORYLATION AT THR-172, AND ACTIVITY REGULATION.
RX PubMed=23332761; DOI=10.1016/j.cell.2012.12.016;
RA Kim J., Kim Y.C., Fang C., Russell R.C., Kim J.H., Fan W., Liu R.,
RA Zhong Q., Guan K.L.;
RT "Differential regulation of distinct Vps34 complexes by AMPK in nutrient
RT stress and autophagy.";
RL Cell 152:290-303(2013).
RN [26]
RP INTERACTION WITH DUSP29, PHOSPHORYLATION AT THR-172, AND SUBCELLULAR
RP LOCATION.
RX PubMed=30201684; DOI=10.2337/db18-0370;
RA Geng T., Liu Y., Xu Y., Jiang Y., Zhang N., Wang Z., Carmichael G.G.,
RA Taylor H.S., Li D., Huang Y.;
RT "H19 lncRNA Promotes Skeletal Muscle Insulin Sensitivity in Part by
RT Targeting AMPK.";
RL Diabetes 67:2183-2198(2018).
RN [27]
RP FUNCTION, AND CATALYTIC ACTIVITY.
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).
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 (By similarity). In response to reduction of
CC intracellular ATP levels, AMPK activates energy-producing pathways and
CC inhibits energy-consuming processes: inhibits protein, carbohydrate and
CC lipid biosynthesis, as well as cell growth and proliferation (By
CC similarity). AMPK acts via direct phosphorylation of metabolic enzymes,
CC and by longer-term effects via phosphorylation of transcription
CC regulators (By similarity). 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:15331533, PubMed:15561936). Promotes lipolysis of lipid
CC droplets by mediating phosphorylation of isoform 1 of CHKA (CHKalpha2)
CC (PubMed:34077757). Regulates insulin-signaling and glycolysis by
CC phosphorylating IRS1, PFKFB2 and PFKFB3 (By similarity). Involved in
CC insulin receptor/INSR internalization (By similarity). AMPK stimulates
CC glucose uptake in muscle by increasing the translocation of the glucose
CC transporter SLC2A4/GLUT4 to the plasma membrane, possibly by mediating
CC phosphorylation of TBC1D4/AS160 (PubMed:16804075, PubMed:16804077).
CC Regulates transcription and chromatin structure by phosphorylating
CC transcription regulators involved in energy metabolism such as
CC CRTC2/TORC2, FOXO3, histone H2B, HDAC5, MEF2C, MLXIPL/ChREBP, EP300,
CC HNF4A, p53/TP53, SREBF1, SREBF2 and PPARGC1A (PubMed:21454484,
CC PubMed:20647423, PubMed:21459323, PubMed:17609368). Acts as a key
CC regulator of glucose homeostasis in liver by phosphorylating
CC CRTC2/TORC2, leading to CRTC2/TORC2 sequestration in the cytoplasm
CC (PubMed:16148943, PubMed:16308421). In response to stress,
CC phosphorylates 'Ser-36' of histone H2B (H2BS36ph), leading to promote
CC transcription (PubMed:20647423). Acts as a key regulator of cell growth
CC and proliferation by phosphorylating TSC2, RPTOR and ATG1/ULK1: in
CC response to nutrient limitation, negatively regulates the mTORC1
CC complex by phosphorylating RPTOR component of the mTORC1 complex and by
CC phosphorylating and activating TSC2 (PubMed:18439900, PubMed:21258367,
CC PubMed:21205641). In response to nutrient limitation, promotes
CC autophagy by phosphorylating and activating ATG1/ULK1 (PubMed:21258367,
CC PubMed:21205641). In that process also activates WDR45/WIPI4 (By
CC similarity). Phosphorylates CASP6, thereby preventing its
CC autoprocessing and subsequent activation (By similarity). AMPK also
CC acts as a regulator of circadian rhythm by mediating phosphorylation of
CC CRY1, leading to destabilize it (PubMed:19833968). May regulate the Wnt
CC signaling pathway by phosphorylating CTNNB1, leading to stabilize it
CC (PubMed:20361929). Also acts as a regulator of cellular polarity by
CC remodeling the actin cytoskeleton; probably by indirectly activating
CC myosin (By similarity). Also phosphorylates CFTR, EEF2K, KLC1, NOS3 and
CC SLC12A1 (By similarity). Plays an important role in the differential
CC regulation of pro-autophagy (composed of PIK3C3, BECN1, PIK3R4 and
CC UVRAG or ATG14) and non-autophagy (composed of PIK3C3, BECN1 and
CC PIK3R4) complexes, in response to glucose starvation (PubMed:23332761).
CC Can inhibit the non-autophagy complex by phosphorylating PIK3C3 and can
CC activate the pro-autophagy complex by phosphorylating BECN1
CC (PubMed:23332761). {ECO:0000250|UniProtKB:P54646,
CC ECO:0000250|UniProtKB:Q09137, ECO:0000269|PubMed:15331533,
CC ECO:0000269|PubMed:15561936, ECO:0000269|PubMed:16148943,
CC ECO:0000269|PubMed:16308421, ECO:0000269|PubMed:16804075,
CC ECO:0000269|PubMed:16804077, ECO:0000269|PubMed:17609368,
CC ECO:0000269|PubMed:18439900, ECO:0000269|PubMed:19833968,
CC ECO:0000269|PubMed:20361929, ECO:0000269|PubMed:20647423,
CC ECO:0000269|PubMed:21205641, ECO:0000269|PubMed:21258367,
CC ECO:0000269|PubMed:21454484, ECO:0000269|PubMed:21459323,
CC ECO:0000269|PubMed:23332761, ECO:0000269|PubMed:34077757}.
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:34077757};
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. Binding
CC of AMP to non-catalytic gamma subunit (PRKAG1, PRKAG2 or PRKAG3)
CC results in allosteric activation, inducing phosphorylation on Thr-172.
CC AMP-binding to gamma subunit also sustains activity by preventing
CC dephosphorylation of Thr-172. ADP also stimulates Thr-172
CC phosphorylation, without stimulating already phosphorylated AMPK. ATP
CC promotes dephosphorylation of Thr-172, rendering the enzyme inactive.
CC Under physiological conditions AMPK mainly exists in its inactive form
CC in complex with ATP, which is much more abundant than AMP. Selectively
CC inhibited by compound C (6-[4-(2-Piperidin-1-yl-ethoxy)-phenyl)]-3-
CC pyridin-4-yl-pyyrazolo[1,5-a] pyrimidine. Activated by resveratrol, a
CC natural polyphenol present in red wine, and S17834, a synthetic
CC polyphenol. Salicylate/aspirin directly activates kinase activity,
CC primarily by inhibiting Thr-172 dephosphorylation.
CC {ECO:0000269|PubMed:15980064, ECO:0000269|PubMed:21459323,
CC ECO:0000269|PubMed:22517326, ECO:0000269|PubMed:23332761}.
CC -!- SUBUNIT: AMPK is a heterotrimer of an alpha catalytic subunit (PRKAA1
CC or PRKAA2), a beta (PRKAB1 or PRKAB2) and a gamma non-catalytic
CC subunits (PRKAG1, PRKAG2 or PRKAG3). Interacts with FNIP1 and FNIP2 (By
CC similarity). Interacts with DUSP29 (PubMed:30201684). {ECO:0000250,
CC ECO:0000269|PubMed:30201684}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:30201684}. Nucleus
CC {ECO:0000250|UniProtKB:P54646}. Note=In response to stress, recruited
CC by p53/TP53 to specific promoters.
CC -!- DOMAIN: The AIS (autoinhibitory sequence) region shows some sequence
CC similarity with the ubiquitin-associated domains and represses kinase
CC activity. {ECO:0000250|UniProtKB:Q13131}.
CC -!- PTM: Ubiquitinated. {ECO:0000269|PubMed:18254724}.
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) (By similarity). {ECO:0000250|UniProtKB:P54646}.
CC -!- DISRUPTION PHENOTYPE: Mice develop obesity when animals are fed a high-
CC fat diet, as a result of an enhanced lipid accumulation in pre-existing
CC adipocytes but not in other tissues. {ECO:0000269|PubMed:15331533}.
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; AL627307; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AL929466; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC138565; AAI38566.1; -; mRNA.
DR EMBL; BC138566; AAI38567.1; -; mRNA.
DR EMBL; AK044030; BAC31746.1; -; mRNA.
DR EMBL; AK134573; BAE22188.1; -; mRNA.
DR CCDS; CCDS18416.1; -.
DR RefSeq; NP_835279.2; NM_178143.2.
DR AlphaFoldDB; Q8BRK8; -.
DR BMRB; Q8BRK8; -.
DR SMR; Q8BRK8; -.
DR BioGRID; 223817; 3.
DR ComplexPortal; CPX-5851; AMPK complex, alpha2-beta2-gamma1 variant.
DR ComplexPortal; CPX-5852; AMPK complex, alpha2-beta1-gamma1 variant.
DR ComplexPortal; CPX-5854; AMPK complex, alpha2-beta2-gamma3 variant.
DR ComplexPortal; CPX-5857; AMPK complex, alpha2-beta1-gamma3 variant.
DR ComplexPortal; CPX-5858; AMPK complex, alpha2-beta1-gamma2 variant.
DR ComplexPortal; CPX-5859; AMPK complex, alpha2-beta2-gamma2 variant.
DR IntAct; Q8BRK8; 2.
DR STRING; 10090.ENSMUSP00000030243; -.
DR BindingDB; Q8BRK8; -.
DR ChEMBL; CHEMBL1255154; -.
DR iPTMnet; Q8BRK8; -.
DR PhosphoSitePlus; Q8BRK8; -.
DR jPOST; Q8BRK8; -.
DR MaxQB; Q8BRK8; -.
DR PaxDb; Q8BRK8; -.
DR PeptideAtlas; Q8BRK8; -.
DR PRIDE; Q8BRK8; -.
DR ProteomicsDB; 296467; -.
DR Antibodypedia; 3399; 843 antibodies from 44 providers.
DR DNASU; 108079; -.
DR Ensembl; ENSMUST00000030243; ENSMUSP00000030243; ENSMUSG00000028518.
DR GeneID; 108079; -.
DR KEGG; mmu:108079; -.
DR UCSC; uc008tyd.2; mouse.
DR CTD; 5563; -.
DR MGI; MGI:1336173; Prkaa2.
DR VEuPathDB; HostDB:ENSMUSG00000028518; -.
DR eggNOG; KOG0583; Eukaryota.
DR GeneTree; ENSGT00940000156945; -.
DR HOGENOM; CLU_000288_59_3_1; -.
DR InParanoid; Q8BRK8; -.
DR OMA; KALNYEW; -.
DR OrthoDB; 1127668at2759; -.
DR PhylomeDB; Q8BRK8; -.
DR TreeFam; TF314032; -.
DR BRENDA; 2.7.11.27; 3474.
DR Reactome; R-MMU-1632852; Macroautophagy.
DR Reactome; R-MMU-163680; AMPK inhibits chREBP transcriptional activation activity.
DR Reactome; R-MMU-200425; Carnitine metabolism.
DR Reactome; R-MMU-380972; Energy dependent regulation of mTOR by LKB1-AMPK.
DR Reactome; R-MMU-5628897; TP53 Regulates Metabolic Genes.
DR Reactome; R-MMU-6804756; Regulation of TP53 Activity through Phosphorylation.
DR BioGRID-ORCS; 108079; 2 hits in 82 CRISPR screens.
DR ChiTaRS; Prkaa2; mouse.
DR PRO; PR:Q8BRK8; -.
DR Proteomes; UP000000589; Chromosome 4.
DR RNAct; Q8BRK8; protein.
DR Bgee; ENSMUSG00000028518; Expressed in triceps brachii and 191 other tissues.
DR Genevisible; Q8BRK8; MM.
DR GO; GO:0016324; C:apical plasma membrane; ISO:MGI.
DR GO; GO:0030424; C:axon; IGI:ARUK-UCL.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0010494; C:cytoplasmic stress granule; IDA:ARUK-UCL.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0030425; C:dendrite; IGI:ARUK-UCL.
DR GO; GO:0005794; C:Golgi apparatus; ISO:MGI.
DR GO; GO:0043025; C:neuronal cell body; IGI:ARUK-UCL.
DR GO; GO:0016607; C:nuclear speck; ISO:MGI.
DR GO; GO:0005654; C:nucleoplasm; TAS:Reactome.
DR GO; GO:0031588; C:nucleotide-activated protein kinase complex; ISO:MGI.
DR GO; GO:0005634; C:nucleus; IDA:MGI.
DR GO; GO:0032991; C:protein-containing complex; ISO:MGI.
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; ISO:MGI.
DR GO; GO:0003682; F:chromatin binding; IDA:UniProtKB.
DR GO; GO:0035174; F:histone serine kinase activity; IDA:UniProtKB.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0004672; F:protein kinase activity; ISO:MGI.
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; ISO:MGI.
DR GO; GO:0044877; F:protein-containing complex binding; ISO:MGI.
DR GO; GO:0030674; F:protein-macromolecule adaptor activity; ISO:MGI.
DR GO; GO:0006914; P:autophagy; IEA:UniProtKB-KW.
DR GO; GO:0071277; P:cellular response to calcium ion; IGI:ARUK-UCL.
DR GO; GO:0042149; P:cellular response to glucose starvation; IDA:UniProtKB.
DR GO; GO:0071333; P:cellular response to glucose stimulus; IGI:ARUK-UCL.
DR GO; GO:0031669; P:cellular response to nutrient levels; IDA:UniProtKB.
DR GO; GO:0034599; P:cellular response to oxidative stress; IGI:ARUK-UCL.
DR GO; GO:0071380; P:cellular response to prostaglandin E stimulus; IGI:MGI.
DR GO; GO:0071466; P:cellular response to xenobiotic stimulus; IMP:MGI.
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; IMP:UniProtKB.
DR GO; GO:0035556; P:intracellular signal transduction; IBA:GO_Central.
DR GO; GO:0008610; P:lipid biosynthetic process; IDA:UniProtKB.
DR GO; GO:1905691; P:lipid droplet disassembly; ISO:MGI.
DR GO; GO:0043066; P:negative regulation of apoptotic process; IMP:UniProtKB.
DR GO; GO:0010629; P:negative regulation of gene expression; IGI:ARUK-UCL.
DR GO; GO:0032007; P:negative regulation of TOR signaling; IMP:UniProtKB.
DR GO; GO:1904428; P:negative regulation of tubulin deacetylation; IGI:ARUK-UCL.
DR GO; GO:0010508; P:positive regulation of autophagy; IMP:UniProtKB.
DR GO; GO:0045821; P:positive regulation of glycolytic process; ISS:UniProtKB.
DR GO; GO:2000758; P:positive regulation of peptidyl-lysine acetylation; IGI:ARUK-UCL.
DR GO; GO:1903829; P:positive regulation of protein localization; IGI:ARUK-UCL.
DR GO; GO:1990044; P:protein localization to lipid droplet; IDA:UniProtKB.
DR GO; GO:0006468; P:protein phosphorylation; IDA:UniProtKB.
DR GO; GO:0042752; P:regulation of circadian rhythm; IMP:UniProtKB.
DR GO; GO:0010468; P:regulation of gene expression; IMP:MGI.
DR GO; GO:0019216; P:regulation of lipid metabolic process; ISO:MGI.
DR GO; GO:0016241; P:regulation of macroautophagy; IDA:UniProtKB.
DR GO; GO:0070507; P:regulation of microtubule cytoskeleton organization; IGI:ARUK-UCL.
DR GO; GO:0062028; P:regulation of stress granule assembly; IGI:ARUK-UCL.
DR GO; GO:0014823; P:response to activity; ISO:MGI.
DR GO; GO:0031000; P:response to caffeine; ISO:MGI.
DR GO; GO:0014850; P:response to muscle activity; IMP:MGI.
DR GO; GO:0048511; P:rhythmic process; IEA:UniProtKB-KW.
DR GO; GO:0016055; P:Wnt signaling pathway; IEA:UniProtKB-KW.
DR CDD; cd14404; UBA_AID_AAPK2; 1.
DR InterPro; IPR032270; AMPK_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 ATP-binding; Autophagy; Biological rhythms; Cholesterol biosynthesis;
KW Cholesterol metabolism; Chromatin regulator; Cytoplasm;
KW Fatty acid biosynthesis; Fatty acid metabolism; Kinase; Lipid biosynthesis;
KW Lipid metabolism; Magnesium; Metal-binding; Nucleotide-binding; Nucleus;
KW Phosphoprotein; Reference proteome; Serine/threonine-protein kinase;
KW Steroid biosynthesis; Steroid metabolism; Sterol biosynthesis;
KW Sterol metabolism; Transcription; Transcription regulation; Transferase;
KW Ubl conjugation; Wnt signaling pathway.
FT CHAIN 1..552
FT /note="5'-AMP-activated protein kinase catalytic subunit
FT alpha-2"
FT /id="PRO_0000262957"
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 ACT_SITE 139
FT /note="Proton acceptor"
FT /evidence="ECO:0000250|UniProtKB:P28523,
FT ECO:0000255|PROSITE-ProRule:PRU00159, ECO:0000255|PROSITE-
FT ProRule:PRU10027"
FT BINDING 22..30
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:P28523,
FT ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 45
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT MOD_RES 172
FT /note="Phosphothreonine; by LKB1 and CaMKK2"
FT /evidence="ECO:0000269|PubMed:15980064,
FT ECO:0000269|PubMed:16308421, ECO:0000269|PubMed:23332761,
FT ECO:0000269|PubMed:30201684"
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:17242355,
FT ECO:0007744|PubMed:21183079"
FT MOD_RES 491
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q09137"
FT MUTAGEN 45
FT /note="K->A: Loss of kinase activity."
FT /evidence="ECO:0000269|PubMed:21454484"
FT MUTAGEN 157
FT /note="D->A: Loss of kinase activity."
FT /evidence="ECO:0000269|PubMed:20647423"
FT CONFLICT 15
FT /note="H -> D (in Ref. 3; BAE22188)"
FT /evidence="ECO:0000305"
FT CONFLICT 289
FT /note="D -> V (in Ref. 3; BAC31746)"
FT /evidence="ECO:0000305"
FT CONFLICT 380
FT /note="A -> E (in Ref. 3; BAE22188)"
FT /evidence="ECO:0000305"
FT CONFLICT 502
FT /note="F -> Y (in Ref. 3; BAE22188)"
FT /evidence="ECO:0000305"
FT CONFLICT 506
FT /note="T -> K (in Ref. 3; BAE22188)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 552 AA; 62022 MW; 020B11E2685BFE39 CRC64;
MAEKQKHDGR VKIGHYVLGD TLGVGTFGKV KIGEHQLTGH KVAVKILNRQ KIRSLDVVGK
IKREIQNLKL FRHPHIIKLY QVISTPTDFF MVMEYVSGGE LFDYICKHGR VEEVEARRLF
QQILSAVDYC HRHMVVHRDL KPENVLLDAQ MNAKIADFGL SNMMSDGEFL RTSCGSPNYA
APEVISGRLY AGPEVDIWSC GVILYALLCG TLPFDDEHVP TLFKKIRGGV FYIPDYLNRS
VATLLMHMLQ VDPLKRATIK DIREHEWFKQ DLPSYLFPED PSYDANVIDD EAVKEVCEKF
ECTESEVMNS LYSGDPQDQL AVAYHLIIDN RRIMNQASEF YLASSPPSGS FMDDSAMHIP
PGLKPHPERM PPLIADSPKA RCPLDALNTT KPKSLAVKKA KWHLGIRSQS KACDIMAEVY
RAMKQLGFEW KVVNAYHLRV RRKNPVTGNY VKMSLQLYLV DSRSYLLDFK SIDDEVVEQR
SGSSTPQRSC SAAGLHRARS SFDSSTAENH SLSGSLTGSL TGSTLSSASP RLGSHTMDFF
EMCASLITAL AR
