Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

AMP-Activated Protein Kinase (AMPK)

  • Gopinath Prakasam
  • Mohammad Askandar Iqbal
  • Rajnish Kumar Singh
  • Rameshwar N. K. Bamezai
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101894


Historical Background

AMPK (5′ adenosine monophosphate-activated protein kinase) (EC; is a cellular energy sensor that is activated by increased intracellular levels of AMP or ADP produced as a result of unrestrained ATP hydrolysis, thus representing scarcity of cellular ATP. AMPK, therefore, allows adaptation to low energy conditions to preserve the cellular energy homeostasis and in response increases catabolism to generate more ATP. Besides acting as a sensor for intracellular metabolic stress signals, due to nutritional insufficiency and hypoxia, AMPK also gets activated by an array of physiological stimulations, including calcium concentration via calmodulin kinase (CAMKKβ), action of various hormones, and cytokines. In brief, once activated by sensing the falling energy (ATP) status, it reprograms the cellular metabolic pathway by increasing the expression or activity of proteins (enzymes) involved in catabolism and on the other hand restricting the energy demanding anabolic pathways to conserve ATP (Fig. 1). AMPK can regulate the energy balance at cellular as well as at whole-body (organismal) level. Though the role of AMPK in metabolism regulation is considered central, it has many other functions, including regulation of mitochondria biogenesis, autophagy, cell polarity, cell growth, and proliferation (Shackelford and Shaw 2009)
AMP-Activated Protein Kinase (AMPK), Fig. 1

Schematic diagram illustrates the elements that impact AMPK activation and its effect on metabolism. LKB1 and CAMKK are two distinct protein kinases that activate bioenergetic sensor, AMPK, by phosphorylating Thr172 residue in response to the surge in AMP/ADP and calcium (Ca2+) concentrations. In addition, AMPK activation is influenced by various stimuli that involves AMPK agonists, activators, hormones, cytokines and reactive oxygen species. The activated AMPK in response to bioenergetic stress reprograms the metabolic phenotype from anabolism to catabolism for rapid energy generation

The first seminal observation on AMPK (primarily named as HMG-CoA reductase kinase) was made in 1973, when the study emphasized about HMG-CoA reductase kinase and the ability to regulate its activity both in vivo and in vitro (Hardie et al. 1994). Shortly after this, researchers realized that the kinase which inactivated HMG-CoA reductase was identical with the one which phosphorylated and inactivated acetyl-CoA carboxylase (ACC), the key regulatory enzyme that controls fatty acid synthesis (Hardie et al. 1994). The term HMG-CoA reductase was collectively replaced by AMP-activated protein kinase after it was shown that the protein kinase could be allosterically activated by 5′ AMP (Ferrer et al. 1985).

The physiological role of AMPK, apart from its role in regulating HMG-CoA reductase and ACC activity (controlling net sterol and fatty acid synthesis pathways) remained unclear for decades. However, with time numerous protein substrates were discovered downstream to AMPK protein kinase, unraveling the unique role of AMPK in sensing and safeguarding cells from environmental stresses and in preserving energy homeostasis. Later findings revealed that AMPK homologues are evolutionarily conserved in all eukaryotes, from yeast to mammals. Snf1 (Sucrose nonfermenting 1), an AMPK homologue in yeast, was shown to serve a pivotal role in maintaining energy homeostasis upon encountering nutritional stress in Saccharomyces cerevisiae (Hardie et al. 1994). A long search of decades for the upstream kinase that phosphorylates AMPK at Thr172 lead to a landmark finding of the heterotrimeric protein complex, a tumor suppressor kinase-liver kinase B1 (LKB1), the pseudokinase STE20-related adaptor (STRAD), and the scaffold protein mouse protein 25 (MO25) (Hardie and Alessi 2013). Further, studies using LKB1 knockout models and tumor cells lacking LKB1 demonstrated that AMPK could still undergo Thr172 phosphorylation by a secondary kinase known as calmodulin-dependent protein kinase kinase β (CaMKKβ) (Hardie et al. 2012).

Structure of AMPK Complex

AMPK, a heterotrimeric serine/threonine protein kinase, consists of alpha, beta, and gamma subunits. Each of the subunit exists in more than one isoform, encoded by independent genes. Protein kinase AMP-activated catalytic subunit alpha1 (PRKAA1) (5p12) and alpha2 (PRKAA2) (1p31) genes code for the two isoforms of α subunit (α1 and α2); whereas, PRKAB1 (12q24) and PRKAB2 (1q21) encode the two isoforms of β subunit (β1 and, β2). PRKAG1 (12q12-q14), PRKAG2 (7q36), and PRKAG3 (2q35), however, code for three isoforms of the γ subunit (γ1, γ2, and γ3) (see Table 1 for more details). The expression of a given subunit isoform and the resultant combination of the heterotrimeric complex is suggested to be cell type and tissue specific. Theoretically, the co-expression of these isoforms could result in 12 combinations of heterotrimeric complexes, though the functional efficiency and relevance of these distinct complexes is unclear (Ross et al. 2016). In the background of distinct heterotrimeric combinations of AMPK in response to diverse stresses, it would be interesting to expedite the structural combinations of different isoforms and their cell type or tissue-specific functional implication.
AMP-Activated Protein Kinase (AMPK), Table 1

AMPK variant details

Subunits of AMPK complex

Gene name

Chromosome loci

Alternate variants

No. of amino acid

Protein size





559 (isoform 1)

64 kDa (isoform 1)

(Entrez 5562)

574 (isoform 2)

65.5 kDa (isoform 2)






62.3 kDa

(Entrez 5563)






30.3 kDa

(Entrez 5564)





272 (isoform 1)

30.3 kDa

(Entrez 5565)

190 (isoform 2)

21.4 kDa





331 (isoform 1)

37.5 kDa

34.0 kDa

(Entrez 5571)

340 (isoform 2)

38.5 kDa

299 (isoform 3)






63.0 kDa


37.5 kDa

(Entrez 51422)


37.5 kDa


58.4 kDa


48.8 kDa






54.2 kDa

(Entrez 53632)

Within a heterotrimeric complex of AMPK, each subunit performs a distinct function, which includes protein kinase activity, stability, and stress sensing (regulation). The alpha subunit of AMPK consists of a typical serine/threonine kinase domain, where its kinase activity depends on Thr172 phosphorylation at the activation loop by the upstream kinases, an autoinhibitory sequence (AIS) and a C-terminal β-subunit interacting domain (β-SID). The β subunits consist of a conserved carbohydrate binding module (CBM) and a carboxyl-terminal αγ subunit binding sequence (αγ-SBS), the latter serves a pivotal role in connecting α and γ subunits to make the core complex. The γ subunit serves as a regulatory domain and contains four tandem repeats of adenine-nucleotide binding sites known as cystathionine beta synthase (CBS) motifs. CBS motifs usually exist as pairs and each pair of CBS motifs is termed as Bateman domain. This regulatory domain of AMPK senses energy status by binding competitively to AMP or ADP during energetic stress and ATP when there is an enormous quantity of nutrient supply and energy production (Fig. 2).
AMP-Activated Protein Kinase (AMPK), Fig. 2

Schematic diagram illustrates the subunits of human AMPK isoforms and their domain organization. The alpha subunits of AMPK involve N-terminal Serine/Threonine protein kinase domain, followed by an autoinhibitory sequence (AIS) and a C-terminal β-subunit interacting domain (β-SID). Thr-172 phosphorylation of N-terminal kinase domain triggers AMPK activation by an upstream kinase. β subunits of AMPK comprise of a carbohydrate binding module (CBM) at the epicenter and a αγ subunit binding sequence (αγ-SBS) at the C-terminal end. γ subunits of AMPK differs by the length of their amino terminal end and contain four nucleotide binding cystathionine beta synthase (CBS) domains numbered 1-4, pairs of CBS domains form two Bateman domains, the latter senses energetic stress by binding AMP/ATP and allosterically regulates AMPK complex

Mechanics of AMPK Activation and Sensing of Energy Stress

Structural studies have demonstrated that at resting phase (normoglycemic and normoxic), the regulatory γ subunit shows preferential binding of ATP to CBS-1, CBS-3, and of AMP to CBS-4. CBS-2 remains unoccupied with adenine nucleotides. While encountering moderate nutritional stress, the ratio of AMP versus ATP within a cell rises gradually and one of the resultant outcomes within the structure of AMPK protein is the replacement of ATP with AMP at CBS-3, which in turn favors phosphorylation of AMP kinase at Thr172 position of the α subunit by AMPKK and protects AMPK from dephosphorylation by phosphatases, stimulating its activity by many fold. However, a severe stress causes replacement of ATP with AMP at CBS-1, resulting in the allosteric activation of AMPK activity.

Once cells recover back from extrinsic and intrinsic stresses and replenish their ATP levels, the bound AMP at CBS sites 1 and 3 of γ subunit is readily replaced with ATP, which in turn promotes dephosphorylation of AMPK at Thr172 and retains its conformation in resting state (Hardie et al. 2012). This mode of AMPK activation in sensing moderate to severe or acute to chronic stress provides graded responses to a wide range of stimuli. Though the allosteric activation of AMPK by cellular AMP has been known for quite some time, the role of ADP in influencing the rate of phosphorylation and de-phosphorylation has been identified in the recent past (Oakhill et al. 2011; Xiao et al. 2011). However with the exception, AMPK in hypothalamic neurons, T cells, and endothelial cells has been shown to be activated predominantly by calcium/calmodulin-dependent kinase kinase 2 (CaMKKβ) in response to the rise in cellular Ca2+ levels, without influencing AMP or ADP concentrations.

In addition to the abovementioned canonical mechanisms responsible for AMPK activation, involving the cellular increase in the concentration of AMP, ADP, and Ca2+, there are reports which demonstrate that TGF-β-activating kinase 1 (TAK1) and reactive oxygen species (e.g., H2O2) could activate AMPK through noncanonical mechanisms. ROS-mediated AMPK activation involves phosphoinositide 3-kinase (PI3K) or ataxia telangiectasia mutated (ATM) signaling pathway (Hardie et al. 2012). Moreover, ATM-mediated activation of AMPK requires LKB1 presence as reflected from studies where abrogation of LKB1 expression resulted in loss of H2O2-mediated AMPK activation. Conversely, studies using cells exposed to DNA damaging agents like etoposide, doxorubicin, and IR (radiation) have demonstrated that ATM can phosphorylate AMPK independent of LKB1.

Pharmacological Agonists That Activate AMPK In Vitro and In Vivo

A variety of natural and synthetic drugs have been shown to differentially activate AMPK. Based upon the mode of AMPK activation, these drugs are categorized in three different major classes (Grahame 2016).

The first category of activators includes (i) drugs, such as (a) glycolysis inhibitor: 2-deoxyglucose (2DG) and (b) inhibitors of mitochondrial-complex I: metformin and phenformin; mitichondrial-complex III: antimycin A; and mitochondrial-complex V: F1 ATP synthase, oligomycin and resveratrol that activate AMPK by modulating the ratio of AMP and ADP by inhibiting ATP synthesis. The second category involves (ii) pro-drugs: (a) 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR), which is cell permeable and is enzymatically converted into ZMP molecule to activate AMPK; (b) C2, a potent synthetic allosteric activator of AMPK, produced from its pro-drug C13 (phosphonate diester) by cellular esterases, preferentially binds and activates AMPK complex containing α1 rather than the α2 isoform; and (c) cordycepin, a natural compound extracted from the fungus, Cordyceps militaris, which is readily permeable in cells and is converted to cordycepin-5′-monophosphate (AMP analog) by cellular enzymes that bind γ subunit of AMPK to activate the protein kinase. The third category, (iii) a class of activators that bind and activate AMPK distinct from AMP-binding site: (a) A-769662 from Abbot Laboratories directly binds AMPK in the cleft situated in-between α subunit kinase domain and CBM of β-subunit. Though A-769662 binding is distinct from that of AMP, however, like AMP, it allosterically activates AMPK and protects it from dephosphorylation of Thr172 (Goransson et al. 2007; Sanders et al. 2007). A-769662 selectively activates AMPK complex that comprises β1 rather than β2 subunit; (b) two compounds, 991(also known as ex229) and MT 63-78, identified by high-throughput screens, that bind the above stated region and allosterically activate AMPK; (c) in addition to the abovementioned synthetic compounds, salicylate, a plant-derived natural product, has also been shown to bind this site and in turn activate AMPK; similar to A-769662, preferentially activating β1 subunit comprising complexes instead of β2 complexes (Hawley et al. 2012).

Role of AMPK in Metabolism

AMPK Regulates Energy Requiring Anabolic Pathways

Upon activation, AMPK reversibly inhibits almost all energy demanding pathways, such as biosynthesis of lipids, proteins, carbohydrates, ribosomal RNA transcription, and cell division, to preserve ATP. The effect of AMPK activation on its downstream targets is either through direct phosphorylation of protein substrates (that entails highly conserved motif with characteristic sequence features) or through the control of transcriptional programs that modulate the expression status of key regulatory proteins (regulatory enzymes) of anabolic pathways. This includes ACC Ser79 phosphorylation which inhibits its role and attenuates the function of mitochondrial glycerol-3-phosphate acyltransferase (GPAT) (involved in phospholipids and triglycerides synthesis) following phosphorylation by AMPK. The 3-hydroxy-3-methylglutaryl CoA reductase (HMGCR) phosphorylation by AMPK blocks its function in cholesterol biosynthesis; whereas, glycogen synthase (GS) phosphorylation at Ser7 residue inhibits glycogen synthesis. Activation of malonyl-CoA decarboxylase by AMPK decreases fatty acid esterification and increases its oxidation. Muscle contraction-induced AMPK phosphorylates hormone-sensitive lipase (HSL), a neutral lipase, which hydrolyzes variety of esters, breaks diacylglycerides to monoglycerides and free fatty acids, which is reviewed in-depth elsewhere (Hardie et al. 2012).

Alternatively, AMPK negatively regulates the expression of lipogenic enzymes FAS (fatty acid synthase) and ACC by downregulating the expression of key transcription factor, sterol regulatory element-binding transcription factor 1 (SREBP-1), or by preventing SREBP1 nuclear translocation and transactivation of lipogenic enzymes by direct phosphorylation. Likewise, AMPK inhibits gluconeogenesis pathway by phosphorylating transcriptional co-activator TORC2 (transducer of regulated CREB activity 2; also known as CRTC2) to prevent its nuclear entry and transcriptional activation of gluconeogenesis enzyme (Shackelford and Shaw 2009). In addition, AMPK phosphorylates and prevents class II histone deacetylase family members in activating FOXO family transcription factors to encode gluconeogenesis enzymes

AMPK Regulates Catabolism for Rapid Energy Generation

The major contribution of AMPK to glucose metabolism involves enhanced glucose uptake and increased glycolytic flux in order to generate energy (ATP) rapidly (Fig. 3). AMPK enables the glucose uptake primarily in contracting muscles by facilitating the translocation of type 4 glucose transporter (GLUT4) to plasma membrane from intracellular storage vesicles. AMPK is directly involved in the trafficking of membrane bound vesicle of GLUT4 transporters by phosphorylating RabGAP-TBC1D1 (TBC1 domain family member 1) to relieve the anchored cargo to fuse with plasma membrane. In addition, AMPK also regulates the translocation of GLUT1. AMPK accelerates the flux of glycolysis by phosphorylating 6-phosphofructo-2-kinase (PFKFB; fructose-2,6-biphosphatase), in particular AMPK phosphorylates isoform PFKFB2 in cardiac myocytes (Marsin et al. 2000) and PFKFB3 in monocytes and macrophages, on sensing ischemic and hypoxic stresses (Marsin et al. 2002). AMPK-mediated phosphorylation of dual functional phosphofructokinase-2 (PFK2) promotes its kinase activity while inhibiting its phosphatase activity to accumulate fructose-2,6-bisphosphate (F26BP), which allosterically activates key rate limiting glycolytic enzyme phosphofructokinase-1 (PFK1) to accelerate the glycolytic flux for energy generation. On the other hand, F26BP inhibits energy consuming gluconeogenesis by allosteric inhibition of enzyme fructose-1,6-bisphosphatase (F1-6BPase).
AMP-Activated Protein Kinase (AMPK), Fig. 3

Role of AMPK in cellular and whole body energy metabolism and homeostasis. AMPK following activation exerts its inhibitory effect on anabolic pathway and promotes catabolic metabolism for energy conservation in tissues of diverse origin. AMPK inhibits the biosynthesis of fatty acid and cholesterol in liver and adipose tissue. In addition, AMPK inhibits; gluconeogenesis in liver, lipolysis in adipose tissue, action potential in neurons, protein synthesis and cell division in cells of multiple tissue origin. Conversely, AMPK stimulates glucose uptake, enhances the rate of glycolysis, fatty acid uptake, fatty acid oxidation and mitochondrial biogenesis in cardiomyocytes and in skeletal muscle cells. AMPK activity in hypothalamus co-ordinates the food intake habit

A study carried out by Prakasam and Bamezai 2016, shown that under nutrient deprived condition AMPK regulates the alternative splicing machinery to favor the expression of pyruvate kinase M1 (PKM1) over M2 (PKM2) isoform in lung and breast cancer cell lines. LKB1 dependent AMPK-mediated preferential expression of PKM1 in cancer cells enhanced the rate of glycolysis and provided endurance against nutrient deprivation (Prakasam and Bamezai 2016).

In cardiomyocytes, AMPK has been shown to promote fatty acid uptake by transporting the membrane bound vesicles harboring CD36 (fatty acid transporter) to plasma membrane, however, the precise mechanism remains obscure. Further, AMPK has been shown to facilitate the export of fatty acid from cytosol to mitochondria for β-oxidation. AMPK achieves this by phosphorylating and inactivating acetyl-coA carboxylase (isoform ACC1 and ACC2) to synthesize malonyl-CoA, a potent inhibitor of carnitine O-palmitoyltransferase. Drop in the level of malonyl-CoA sets carnitine O-palmitoyltransferase free to export fatty acid to mitochondria followed by β-oxidation, an energy generating process (Hardie et al. 2012)

AMPK in Mitochondrial Biogenesis, Autophagy, and Mitophagy

The connecting link of AMPK with mitochondrial biogenesis is elucidated from studies on rats fed with AICAR (AMPK agonist). These rats demonstrated increased mitochondrial gene expression, especially in the cells of muscle origin. Further, extensive studies carried out using double knockout mice models for AMPK-β1 and AMPK-β2, have exhibited attenuated AMPK activity in muscle and reduced mitochondrial content or biogenesis. Peroxisome proliferator-activated receptor-γ coactivator 1α (PGC1α), the master regulator of mitochondrial biogenesis, plays an indispensable role in regulating the expression of nuclear-encoded mitochondrial genes by serving as a transcriptional coactivator. AMPK phosphorylates PGC1α at Thr177 and Ser538 residues to induce the expression of GLUT4, nuclear-encoded mitochondrial genes and self-regulates its own expression through a positive feedback loop. In addition, through a distinct mechanism AMPK enhances mitochondrial biogenesis, which involves deacetylation of PGC1α by NAD-dependent deacetylase sirtuin I (SIRT1) (Canto et al. 2010).

Besides mitochondrial biogenesis, AMPK is also involved in the recycling of nonfunctional mitochondria by selectively targeting them through autophagy known as mitophagy. AMPK executes this function by interacting and phosphorylating master regulator of autophagy, UNC-52-like kinase 1 (ULK1), orthologue of yeast Atg1 (Behrends et al. 2010; Egan et al. 2011). AMPK and ULK1 axis through mitophagy eliminate aberrant mitochondria which undergo oxidative damage and restore new ones by mitochondrial biogenesis to increase the oxidative catabolic endurance of cells to meet energy paucity.

Role of AMPK Beyond Metabolism

AMPK, mTOR, and Protein Synthesis

AMPK controls net protein translation rate under the nutrient-deprived circumstances by negatively regulating mammalian target of rapamycin (mTOR). mTOR, a highly conserved serine/threonine protein kinase, which couples the available growth factor and nutrient signaling to stimulate protein synthesis and cell growth (Guertin and Sabatini 2007). Active mTOR complex plays a vital role in controlling the assembly of translation initiation by recruiting and phosphorylating its well characterized substrates, 4EBP1 and p70 ribosomal S6 kinase (S6K). Active AMPK exerts its inhibitory effects on mTOR and its protein translation mechanism through Tuberous sclerosis complex 2 (TSC2 or tuberin). TSC2 and its obligate partner TSC1 inhibit MTORC1 (mTOR complex 1) through the regulation of small GTPase Ras homologue enriched in brain (RHEB). Moreover, AMPK has been shown to directly phosphorylate raptor (regulatory associated protein of mTOR) subunit of mTORC1 and promote raptor to bind 14-3-3, thus decreasing the mTOR activity.

AMPK and Cell Cycle Checkpoints

Like protein synthesis, cell division is also a high energy demanding processes. AMPK, in order to conserve energy, creates cell division checkpoints in cells that meet energy deficiency. Studies have demonstrated the characteristic ability of AMPK to directly phosphorylate P53 at Ser15 residue and cyclin-dependent kinase inhibitor P27 at Thr198 residue to block cell cycle upon limited nutrient supply (Jones et al. 2005). In addition, AMPK phosphorylates Ser36 residue of histone2B (H2B) at the promoter and coding region of stress-associated genes, p21 and cpt1c, to regulate their expression for stress adaptation. On the contrary, Banko et al., using chemical genetic screen, have revealed the key role of AMPK in progression of mitosis and cytokinesis, via the phosphorylation of protein phosphatase 1 regulatory subunit 12C (PPP1R12C), suggesting the importance of the energy sensor, AMPK, in the accomplishment of mitosis (Banko et al. 2011).

Control of Cell Polarity, Migration, and Cytoskeletal Dynamics by AMPK

Studies in recent past have found remarkable interconnecting links of AMPK pathway with cell polarity and cytoskeletal dynamics (Mihaylova and Shaw 2011). Loss of AMPK in drosophila has shown abnormal cell polarity and mitosis. It was anticipated that loss of AMPK abrogates phosphorylation on myosin light Chain (MLC), a key event that regulates cell polarity and mitotic cell division. The involvement of activated AMPK following calcium switch and their role in tight junction formation was reported by using mammalian MDCK cell lines. It has been reported that afadin, an adherens junction protein, and GBF1 (Golgi-specific brefeldin A resistance factor 1), a guanine nucleotide exchange factor for the ADP-ribosylation factor family, act as putative downstream substrates of AMPK, proposed to be involved in regulating cell polarity.

AMPK and Organism Physiology

In addition to its confined role at cellular level, AMPK exerts major biochemical and behavioral changes at whole-body level to preserve energy homeostasis. For instance, AMPK activity in hypothalamus regulates appetite. The factors that induce appetite, such as ghrelin, adiponectin (adipokine), or cannabinoids, enhance AMPK activity in the hypothalamus. Whereas, hormones that inhibit eating (anorexigenic or appetite suppressant) such as leptin and insulin inhibit AMPKα2 activity in the hypothalamus (Fig. 3). Notably, administration of AMPK agonist or AMPK constitutively active mutants in the hypothalamus have shown to induce hunger. In recent studies it has been shown that ghrelin activates AMPK through Ca2+ dependent CaMKKβ kinase in presynaptic neurons upstream of NPY/AgRP neurons in the hypothalamus, which in turn triggers a positive feedback loop of continued neurotransmitter release for an urge to eat; whereas, leptin after feeding activates pro-opiomelanocortin (POMC) neurons to release opioids, halting the AMPK activation in the presynaptic neurons (reviewed in depth (Hardie et al. 2012)).

AMPK and Membrane Excitability

It has been estimated that approximately 25–50% of energy is consumed for firing action potential followed by synaptic transmission. AMPK, in order to preserve energy homeostasis in nutritionally compromised neuronal tissues, limits the rate of action potential (Attwell and Laughlin 2001). Recent study using in vitro model system has shown that AMPK phosphorylates two distinct amino acid residues of Kv2.1 potassium channel in its C-terminal tail, resulting in a shift in voltage gating towards more negative membrane potential. This in turn reduces the firing of action potential down the axon (Ikematsu et al. 2011).

AMPK and Circadian Cycle

Recent studies have also established a connecting link between AMPK pathway and circadian clock, which senses the day/night cycle and regulates the coordinated transcriptional programs to control the systemic physiology. Remarkably, AMPK has been shown to regulate cryptochrome circadian clock 1 (Cry1 – a core clock component protein) turnover, where phosphorylation by AMPK directs Cry1 towards ubiquitin-mediated proteasomal degradation in F-box protein Fbx13 (an E3 ubiquitin ligase) dependent manner (Lamia et al. 2009). In another study, AMPK has been shown to phosphorylate casein kinase 1 (CKIepsilon) at Ser389 residue that results in its increased activity and degradation of circadian clock component mPer2 (Um et al. 2007). Finally, studies using AMPK alpha subunit specific knockout models have revealed the significant role of AMPK in regulating circadian rhythm of energy metabolism and behavior to different extents, based on the isoform- and tissue-specific context (Um et al. 2011).

Unconventional Roles of AMPK: Beyond Energy Homeostasis and Metabolism

V(D)J Recombination

Accumulating evidence has emerged to demonstrate the ancillary function of AMPK beyond metabolism and energy homeostasis. A recent study carried out by Um et al. demonstrated the role of metabolic stress sensor, AMPK in V(D)J recombination and in the development of T and B lymphocytes, where AMPK was shown to directly phosphorylate recombinant-activating gene 1 protein (RAG1) at Ser528 residue to enhance its catalytic activity of cleavage of oligonucleotide substrates (Um et al. 2013).


Dietary restriction and well-characterized agonist or activator of AMPK, like resveratrol and metformin, have been shown to enhance the longevity of C. elegans. In addition genetic deletion screens have validated the role played by AMPK orthologues in life-extending effects (Greer and Brunet 2009; Onken and Driscoll 2010).


The free energy released upon the hydrolysis of ATP is the only source of energy that drives almost all the energy-requiring processes. Therefore, a dynamic balance between ATP production and consumption is to be maintained in order to modulate the ATP production or consumption in accordance to the needs of the cell. AMPK executes a perfect role by sensing the energy stress through AMP or ADP and rewiring the metabolic pathways to promote ATP production while conserving ATP by switching off biosynthetic pathways (Hardie et al. 2012). This cellular “energy sensor,” AMPK, is believed to be an ancient old protein kinase system which may have come into existence at least a billion year ago to protect cells against the effects of nutritional or environmental stress. Accordingly, AMPK homologues are evolutionarily conserved from yeast, nematodes, and plants to mammals (Hardie and Carling 1997). Extensive research in recent years has revealed crucial roles of AMPK in modulating almost all biological pathways that include energy production or consumption. However, comprehensive characterization of emerging putative AMPK targets that have been reported using in vitro studies require further validation in in vivo conditions, using AMPK knockout models. The broad spectrum of AMPK activities in lipid and glucose metabolism makes it a very attractive target for drug discovery. Ever since AMPK has been shown to regulate lipid, cholesterol, and glucose metabolism in specialized metabolic tissues, such as liver, muscle, and adipose tissue, it is considered as a key therapeutic target in metabolic diseases, like diabetes and cancer. Remarkably, epidemiological studies involving type 2 diabetes patients have shown a statistical reduction in tumor incidence with consumption of AMPK activators (metformin) (Shaw 2006). The connecting links between AMPK and several tumor suppressors, like p53, TSC1/2, and LKB1, suggest that therapeutic manipulation of this pathway using established antidiabetes drugs alone or in combination with other anticancer drugs could provide a therapeutics strategy to curtail cancer. In summary, the extent of AMPK functionality makes it a very important molecule with immense therapeutic potential.


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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Gopinath Prakasam
    • 1
  • Mohammad Askandar Iqbal
    • 1
    • 2
  • Rajnish Kumar Singh
    • 1
    • 3
  • Rameshwar N. K. Bamezai
    • 1
  1. 1.National Center for Applied Human Genetics, School of Life SciencesJawaharlal Nehru UniversityNew DelhiIndia
  2. 2.Department of Biotechnology, Faculty of Natural SciencesJamia Millia IslamiaNew DelhiIndia
  3. 3.Department of Microbiology and Tumor Virology Program of the Abramson Cancer Center, Perelman School of MedicineUniversity of PennsylvaniaPhiladelphiaUSA