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 27-MAR-2024, entry version 173. 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 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 Medulla RC 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 RC 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. RX PubMed=32912901; DOI=10.1101/gad.339895.120; RA Van Nostrand J.L., Hellberg K., Luo E.C., Van Nostrand E.L., Dayn A., RA Yu J., Shokhirev M.N., Dayn Y., Yeo G.W., Shaw R.J.; RT "AMPK regulation of Raptor and TSC2 mediate metformin effects on RT transcriptional control of anabolism and inflammation."; RL Genes Dev. 34:1330-1344(2020). RN [28] 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 FNIP1, TSC2, RPTOR, WDR24 and CC ATG1/ULK1: in response to nutrient limitation, negatively regulates the CC mTORC1 complex by phosphorylating RPTOR component of the mTORC1 complex CC and by phosphorylating and activating TSC2 (PubMed:18439900, CC PubMed:21258367, PubMed:21205641, PubMed:32912901). Also phosphorylates CC and inhibits GATOR2 subunit WDR24 in response to nutrient limitation, CC leading to suppress glucose-mediated mTORC1 activation (By similarity). CC In response to energetic stress, phosphorylates FNIP1, inactivating the CC non-canonical mTORC1 signaling, thereby promoting nuclear translocation CC of TFEB and TFE3, and inducing transcription of lysosomal or autophagy CC genes (By similarity). 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). Upon glucose starvation, promotes ARF6 activation in CC a kinase-independent manner leading to cell migration (By similarity). CC Upon glucose deprivation mediates the phosphorylation of ACSS2 at 'Ser- CC 659', which exposes the nuclear localization signal of ACSS2, required CC for its interaction with KPNA1 and nuclear translocation (By CC similarity). {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:32912901, CC 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; 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). Interacts with CC ARF6 (By similarity). The phosphorylated form at Thr-172 mediated by CC CamKK2 interacts with ACSS2 (By similarity). CC {ECO:0000250|UniProtKB:P54646, 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}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; 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 GlyGen; Q8BRK8; 1 site, 1 O-linked glycan (1 site). DR iPTMnet; Q8BRK8; -. DR PhosphoSitePlus; Q8BRK8; -. DR SwissPalm; Q8BRK8; -. DR jPOST; Q8BRK8; -. DR MaxQB; Q8BRK8; -. DR PaxDb; 10090-ENSMUSP00000030243; -. DR PeptideAtlas; Q8BRK8; -. DR ProteomicsDB; 296467; -. DR Antibodypedia; 3399; 991 antibodies from 44 providers. DR DNASU; 108079; -. DR Ensembl; ENSMUST00000030243.8; ENSMUSP00000030243.8; ENSMUSG00000028518.9. DR GeneID; 108079; -. DR KEGG; mmu:108079; -. DR UCSC; uc008tyd.2; mouse. DR AGR; MGI:1336173; -. 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; SKTKWHF; -. DR OrthoDB; 5475340at2759; -. 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 Reactome; R-MMU-9759194; Nuclear events mediated by NFE2L2. DR BioGRID-ORCS; 108079; 2 hits in 88 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 193 other cell types or tissues. 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:0140823; F:histone H2BS36 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: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:1903944; P:negative regulation of hepatocyte apoptotic process; ISO:MGI. DR GO; GO:0032007; P:negative regulation of TOR signaling; IMP:UniProtKB. DR GO; GO:1904262; P:negative regulation of TORC1 signaling; IDA: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; cd14079; STKc_AMPK_alpha; 1. DR CDD; cd14404; UBA_AID_AAPK2; 1. DR Gene3D; 1.10.8.10; DNA helicase RuvA subunit, C-terminal domain; 1. DR Gene3D; 3.30.310.80; Kinase associated domain 1, KA1; 1. DR Gene3D; 1.10.510.10; Transferase(Phosphotransferase) domain 1; 1. DR InterPro; IPR032270; AMPK_C. DR InterPro; IPR028375; KA1/Ssp2_C. DR InterPro; IPR011009; Kinase-like_dom_sf. DR InterPro; IPR049020; PRKAA1/2_AID. DR InterPro; IPR028783; PRKAA2. DR InterPro; IPR000719; Prot_kinase_dom. DR InterPro; IPR017441; Protein_kinase_ATP_BS. DR InterPro; IPR008271; Ser/Thr_kinase_AS. DR PANTHER; PTHR24346; MAP/MICROTUBULE AFFINITY-REGULATING KINASE; 1. DR PANTHER; PTHR24346:SF82; SERINE_THREONINE-PROTEIN KINASE MARK-A-RELATED; 1. DR Pfam; PF16579; AdenylateSensor; 1. DR Pfam; PF21147; AMPK_alpha_AID; 1. DR Pfam; PF00069; Pkinase; 1. DR SMART; SM00220; S_TKc; 1. DR SUPFAM; SSF103243; KA1-like; 1. DR SUPFAM; SSF56112; Protein kinase-like (PK-like); 1. DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1. DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1. DR PROSITE; PS00108; PROTEIN_KINASE_ST; 1. DR Genevisible; Q8BRK8; MM. 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 //