Alternative titles; symbols
HGNC Approved Gene Symbol: PRKAA2
Cytogenetic location: 1p32.2 Genomic coordinates (GRCh38): 1:56,645,314-56,715,335 (from NCBI)
AMP-activated protein kinase plays a key role in the regulation of fatty acid and cholesterol metabolism (Hardie, 1992; Hardie and MacKintosh, 1992). In vitro, it phosphorylates and inactivates 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR; 142910) and acetyl-CoA carboxylase (ACC; 200350), key enzymes involved in regulating de novo biosynthesis of cholesterol and fatty acids, respectively. See PRKAA1 (602739) for additional background.
Beri et al. (1994) used a cDNA encoding rat liver AMPK to isolate human skeletal muscle AMPK cDNA clones. The human cDNA was more than 90% homologous to the rat sequence and predicted a protein of 62.3 kD that closely agreed with the mass of human AMPK observed in Western blots of human tissue extracts. A cDNA probe was used to identify a 9.5-kb transcript in several human tissues and to isolate human genomic clones. Stapleton et al. (1997) showed that rat liver Ampk-alpha-2 is associated with Ampk-beta-1 (PRKAB1; 602740) and Ampk-gamma-1 (PRKAG1; 602742). They noted that Ampk-alpha-1 (PRKAA1) is also associated with these beta and gamma isoforms.
Beri et al. (1994) used PCR mapping of rodent/human hybrid cell lines to localize the human AMPK gene to chromosome 1, and they sublocalized the AMPK gene to 1p31 by fluorescence in situ hybridization with a human genomic clone. (The cDNA referred to as AMPK by Beri et al. (1994) encodes the alpha-2 subunit of AMPK.)
Tsujikawa et al. (1998) determined that PRKAA2 and the CDC-like kinase-2 gene (CLK2; 602989) are located in the same interval of approximately 2.6 cM between D1S2890 and D1S2801. They suggested that CLK2 and PRKAA2 are possible candidate genes for gelatinous drop-like corneal dystrophy (204870).
Mu et al. (2001) investigated the role of the metabolic sensor AMPK in the regulation of glucose transport in skeletal muscle. Expression in mouse muscle of a dominant inhibitory mutant of Ampk-alpha-2 completely blocked the ability of hypoxia and 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) to activate hexose uptake, while only partially reducing contraction-stimulated hexose uptake. These data indicated that AMPK transmits a portion of the signal by which muscle contraction increases glucose uptake, but other AMPK-independent pathways also contribute to the response.
Minokoshi et al. (2002) demonstrated that leptin (164160) selectively stimulates phosphorylation and activation of AMPK-alpha-2 in skeletal muscle, thus establishing an additional signaling pathway for leptin. Early activation of AMPK occurs by leptin acting directly on muscle, whereas later activation depends on leptin functioning through the hypothalamic-sympathetic nervous system axis. In parallel with its activation of AMPK, leptin suppresses the activity of ACC (200350, 601557), thereby stimulating the oxidation of fatty acids in muscle. Blocking AMPK activation inhibits the phosphorylation of ACC stimulated by leptin. Minokoshi et al. (2002) concluded that their data identify AMPK as a principal mediator of the effects of leptin on fatty acid metabolism in muscle.
Hoyer-Hansen et al. (2007) showed that Ca(2+)-induced autophagy in mammalian cells utilized a signaling pathway that included CAMKK2, AMPK, and mTOR (FRAP1; 601231). Ca(2+)-induced autophagy was inhibited by BCL2 (151430) but only when BCL2 was localized to the endoplasmic reticulum.
Known as the 'fuel gauge of the cell' (Hardie and Carling, 1997), AMPK is activated by an increase in the cellular AMP:ATP ratio after ATP depletion. Once activated, AMPK switches on ATP-generating (catabolic) pathways and switches off ATP-consuming (anabolic) pathways, allowing the cell to restore its energy balance. Spencer-Jones et al. (2006) hypothesized that the serum lipid profile may be influenced by genetic variation in the AMPK catalytic alpha-2 subunit. They examined 5 tagging SNPs in the PRKAA2 gene with serum lipids in 2,777 normal Caucasian females and found a significant association.
Randriamboavonjy et al. (2010) found that human and mouse platelets expressed AMPK-alpha-1 and AMPK-alpha-2 and that thrombin (F2; 176930) elicited threonine phosphorylation of AMPK-alpha and the upstream kinase LKB1 (STK11; 602216). In human platelets, kinase inhibition blocked thrombin-induced platelet aggregation and clot retraction without affecting the initial increase in intracellular calcium. Clot retraction was also impaired in platelets from Ampk-alpha-2 -/- mice, but not in platelets from wildtype littermates or Ampk-alpha-1 -/- mice. Tail bleeding times were not altered by Ampk-alpha-2 deletion, but rebleeding was more frequent and ferric chloride-induced thrombi were unstable in Ampk-alpha-2 -/- mice. Ampka-alpha-2 threonine phosphorylated Fyn (137025), and deletion of Ampka-alpha-2 reduced phosphorylation of Fyn and the Fyn substrate beta-3 integrin (ITGB3; 173470). Randriamboavonjy et al. (2010) concluded that AMPK-alpha-2 in platelets has a role in clot retraction and thrombus stability by regulating FYN-mediated phosphorylation of beta-3 integrin.
Viollet et al. (2003) generated an AMPK-alpha-2 catalytic subunit knockout mouse model. Prkaa2 -/- mice appeared indistinguishable from their control littermates, but exhibited glucose intolerance in vivo secondary to reduced insulin release and decreased insulin sensitivity of peripheral tissues. The metabolic function of AMPK-alpha-2 in isolated skeletal muscle and pancreatic islets was normal, however, suggesting that the origin of the defects observed in vivo was located outside these tissues. There was significant increased catecholamine excretion in Prkaa2 -/- mice. Viollet et al. (2003) hypothesized that the lack of AMPK-alpha-2 in neurons reduced the ability to integrate peripheral metabolic signals into the brain, leading to altered control of peripheral insulin sensitivity and insulin secretion by increasing sympathetic nervous activity.
Beri, R. K., Marley, A. E., See, C. G., Sopwith, W. F., Aguan, K., Carling, D., Scott, J., Carey, F. Molecular cloning, expression and chromosomal localisation of human AMP-activated protein kinase. FEBS Lett. 356: 117-121, 1994. [PubMed: 7988703] [Full Text: https://doi.org/10.1016/0014-5793(94)01247-4]
Hardie, D. G. Regulation of fatty acid and cholesterol metabolism by the AMP-activated protein kinase. Biochim. Biophys. Acta 1123: 231-238, 1992. [PubMed: 1536860] [Full Text: https://doi.org/10.1016/0005-2760(92)90001-c]
Hardie, D. G., Carling, D. The AMP-activated protein kinase: fuel gauge of the mammalian cell? Europ. J. Biochem. 246: 259-273, 1997. [PubMed: 9208914] [Full Text: https://doi.org/10.1111/j.1432-1033.1997.00259.x]
Hardie, D. G., MacKintosh, R. W. AMP-activated protein kinase: an archetypal protein kinase cascade? Bioessays 14: 699-704, 1992. [PubMed: 1365882] [Full Text: https://doi.org/10.1002/bies.950141011]
Hoyer-Hansen, M., Bastholm, L., Szyniarowski, P., Campanella, M., Szabadkai, G., Farkas, T., Bianchi, K., Fehrenbacher, N., Elling, F., Rizzuto, R., Mathiasen, I. S., Jaattela, M. Control of macrophagy by calcium, calmodulin-dependent kinase kinase-beta, and Bcl-2. Molec. Cell 25: 193-205, 2007. [PubMed: 17244528] [Full Text: https://doi.org/10.1016/j.molcel.2006.12.009]
Minokoshi, Y., Kim, Y.-B., Peroni, O. D., Fryer, L. G. D., Muller, C., Carling, D., Kahn, B. B. Leptin stimulates fatty-acid oxidation by activating AMP-activated protein kinase. Nature 415: 339-343, 2002. [PubMed: 11797013] [Full Text: https://doi.org/10.1038/415339a]
Mu, J., Brozinick, J. T., Jr., Valladares, O., Bucan, M., Birnbaum, M. J. A role for AMP-activated protein kinase in contraction- and hypoxia-regulated glucose transport in skeletal muscle. Molec. Cell 7: 1085-1094, 2001. [PubMed: 11389854] [Full Text: https://doi.org/10.1016/s1097-2765(01)00251-9]
Randriamboavonjy, V., Isaak, J., Fromel, T., Viollet, B., Fisslthaler, B., Preissner, K. T., Fleming, I. AMPK alpha-2 subunit is involved in platelet signaling, clot retraction, and thrombus stability. Blood 116: 2134-2140, 2010. [PubMed: 20558612] [Full Text: https://doi.org/10.1182/blood-2010-04-279612]
Spencer-Jones, N. J., Ge, D., Snieder, H., Perks, U., Swaminathan, R., Spector, T. D., Carter, N. D., O'Dell, S. D. AMP-kinase alpha-2 subunit gene PRKAA2 variants are associated with total cholesterol, low-density lipoprotein-cholesterol and high-density lipoprotein-cholesterol in normal women. (Letter) J. Med. Genet. 43: 936-942, 2006. [PubMed: 16801347] [Full Text: https://doi.org/10.1136/jmg.2006.041988]
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. [PubMed: 9224708] [Full Text: https://doi.org/10.1016/s0014-5793(97)00569-3]
Tsujikawa, M., Kurahashi, H., Tanaka, T., Okada, M., Yamamoto, S., Maeda, N., Watanabe, H., Inoue, Y., Kiridoshi, A., Matsumoto, K., Ohashi, Y., Kinoshita, S., Shimomura, Y., Nakamura, Y., Tano, Y. Homozygosity mapping of a gene responsible for gelatinous drop-like corneal dystrophy to chromosome 1p. Am. J. Hum. Genet. 63: 1073-1077, 1998. [PubMed: 9758629] [Full Text: https://doi.org/10.1086/302071]
Viollet, B., Andreelli, F., Jorgensen, S. B., Perrin, C., Geloen, A., Flamez, D., Mu, J., Lenzner, C., Baud, O., Bennoun, M., Gomas, E., Nicolas, G., Wojtaszewski, J. F. P., Kahn, A., Carling, D., Schuit, F. C., Birnbaum, M. J., Richter, E. A., Burcelin, R., Vaulont, S. The AMP-activated protein kinase alpha-2 catalytic subunit controls whole-body insulin sensitivity. J. Clin. Invest. 111: 91-98, 2003. [PubMed: 12511592] [Full Text: https://doi.org/10.1172/JCI16567]