id: PW:0000542 rgd_url: https://rgd.mcw.edu/rgdweb/pathway/pathwayRecord.html?processType=view&species=Rat&acc_id=PW:0000542 title: adenosine monophosphate-activated protein kinase (ampk) signaling pathway description: AMPK signaling pathway, a fuel sensor and regulator, promotes ATP-producing and inhibits ATP-consuming pathways in various tissues. AMPK is a heterotrimer composed of alpha-catalytic and beta and gamma-regulatory subunits. Humans and rodents have two alpha and beta and three gamma isoforms; some genes are subject to alternative splicing increasing the range of possible heterotrimer combinations. Cellular stresses that inhibit ATP production or increase its consumption change the AMP:ATP ratio and activate the pathway. AMPK activation by AMP is not completely understood; the current model states that binding of AMP to the gamma subunit leads to conformational changes that allosterically activate AMPK and render phosphorylated-Thr172 unavailable for inhibitory dephosphorylation. ATP antagonizes the effect of AMP; both AMP and ATP bind in a mutually exclusive manner to the Bateman ( CBS ) domains of the gamma subunit. There are four tandem repeats of CBS number 1-4; site 2 is empty, site 4 has a bound AMP molecule, sites 1 and 3 are the regulatory sites that competitively bind AMP, ADP or ATP. Binding of AMP to site 1 is believed to confer allosteric activation while binding of AMP or ADP to site 3 is thought to protect threonine 172 from dephosphorylation. The upstream kinase, known as Lkb1, is a complex of one catalytic and two regulatory subunits; Lkb1 is believed to be 'constitutively active'. In certain cell types, Thr172 can be phosphorylated by calmodulin-dependent protein kinase kinases (CAmKK), in turn activated by calcium/calmodulin. A well known role of AMPK is in the regulation of lipid metabolism; it stimulates fatty acids oxidation and inhibits their synthesis. Phosphorylation by AMPK inhibits acetyl-CoA carboxylase (ACC) and results in reduced levels of malonyl-CoA product. Malonyl CoA is a substrate in the de novo synthesis of fatty acids and fatty acids elongation. Importantly, it is also an inhibitor of the carnitine palmitoyl transferase I, required for the transfer of primed cytosolic fatty acids into the mitochondrion where they can undergo degradative beta-oxidation. AMPK inhibits mTOR signaling pathway by activating Tsc2 and downstream of Tsc2 by inhibiting Raptor component of mTOR complex 1 [note that this effect is opposite to Tsc2 phosphorylation and inactivation by PI3K-Akt signaling downstream of insulin]. AMPK is also involved in promoting glucose uptake and utilization and integrates adipokynes and hormonal signals in both the hypothalamus and the periphery with potential impact on energy expenditure. A target of AMPK is TBC1D1, a protein related to TBC1D4, the Rab protein GAP involved in glucose uptake in insulin sensitive tissues. Rabs are small monomeric G-proteins involved in vesicular transport; they are activated by GTP exchange factors (GEFs) and inactivated by GTPase activator proteins (GAPs). Due to its roles in fuel regulation, the AMPK pathway is regarded as a potential therapeutic target for Diabetes Mellitus type 2 (T2D), obesity and metabolic syndrome. Drugs used in the treatment of insulin resistance and diabetes can activate AMPK. For instance, metformin - an antihyperglycemic drug used in the first-line treatment of T2D activates AMPK signaling, albeit indirectly. The primary target of metformin is the complex I of the respiratory chain; lowering of the proton gradient and reduction of the proton-driven synthesis of ATP will lead to a change in the AMP:ATP ratio. diagram_image: https://rgd.mcw.edu/pathway/PW0000542/adenosine%20monophosphate-activated%20protein%20kinase%20(AMPK)%20signaling%20pathway/pwmap.png pathway_studio_file: https://rgd.mcw.edu/pathway/PW0000542/adenosine%20monophosphate-activated%20protein%20kinase%20(AMPK)%20signaling%20pathway/adenosine%20monophosphate-activated%20protein%20kinase%20(AMPK)%20signaling%20pathway.gpp diagram_pathway_links: - id: PW:0000029 label: fatty acid biosynthetic pathway - id: PW:0000180 label: mTOR signaling pathway - id: PW:0000532 label: glycogen biosynthetic pathway - id: PW:0000639 label: insulin responsive facilitative sugar transporter mediated glucose transport pathway - id: PW:0000641 label: gluconeogenesis pathway - id: PW:0000738 label: fatty acid beta degradation pathway diagram_gene_links: - id: RGD:62023 label: Camkk1 - id: RGD:620092 label: Camkk2 - id: RGD:735028 label: Ppm1e - id: RGD:631363 label: Ppm1f - id: RGD:3380 label: Ppp2ca diagram_chemicals: - id: CHEBI:16761 label: ADP - id: CHEBI:16027 label: AMP - id: CHEBI:15422 label: ATP - id: CHEBI:29108 label: Ca2+ diagram_edges: - source: ADP relation: associated_with target: AMPK gamma - source: AMP relation: associated_with target: AMPK gamma - source: AMPK alpha relation: associated_with target: AMPK beta - source: AMPK alpha relation: positively_affects target: AMPK targets - source: AMPK beta relation: associated_with target: AMPK gamma - source: AMPK gamma relation: associated_with target: ATP - source: AMPK targets relation: negatively_affects target: fatty acid biosynthetic pathway - source: AMPK targets relation: negatively_affects target: gluconeogenesis pathway - source: AMPK targets relation: negatively_affects target: glycogen biosynthetic pathway - source: AMPK targets relation: negatively_affects target: mTOR signaling pathway - source: PP1 in AMPK relation: negatively_affects target: AMPK alpha - source: Ppm1e relation: negatively_affects target: AMPK alpha - source: Ppm1f relation: negatively_affects target: AMPK alpha - source: Ppp2ca relation: negatively_affects target: AMPK alpha - source: calmodulin relation: associated_with target: Camkk1 - source: calmodulin relation: associated_with target: Camkk2 - source: cellular stress relation: positively_affects target: ADP - source: cellular stress relation: positively_affects target: AMP - source: cellular stress relation: positively_affects target: ATP diagram_labels: - AMP --+> AMPK gamma - AMPK targets --+> fatty acid beta degradation pathway - AMPK targets --+> insulin responsive facilitative sugar transporter mediated glucose transport pathway - Camkk1 --+> AMPK alpha - Camkk2 --+> AMPK alpha - cellular stress - Lkb1 complex --+> AMPK alpha - P-T172 diagram_other_links: - href: /wg/home/pathway2/molecular-pathways2/ampk-alpha label: AMPK alpha - href: /wg/home/pathway2/molecular-pathways2/ampk-beta label: AMPK beta - href: /wg/home/pathway2/molecular-pathways2/ampk-gamma label: AMPK gamma - href: /wg/home/pathway2/molecular-pathways2/ampk-targets label: AMPK targets - href: /wg/home/pathway2/molecular-pathways2/calmodulin label: calmodulin - href: /wg/home/pathway2/molecular-pathways2/lkb1-complex2 label: Lkb1 complex - href: /wg/home/pathway2/molecular-pathways2/pp1-in-ampk label: PP1 in AMPK references: - id: RGD:1600678 citation: Hardie DG J Cell Sci. 2004 Nov 1;117(Pt 23):5479-87. - id: RGD:5129820 citation: Kahn BB, etal., Cell Metab. 2005 Jan;1(1):15-25. - id: RGD:5129859 citation: Ruderman NB and Saha AK, Obesity (Silver Spring). 2006 Feb;14 Suppl 1:25S-33S. - id: RGD:5129878 citation: Hardie DG Annu Rev Pharmacol Toxicol. 2007;47:185-210. - id: RGD:5130005 citation: Rutter GA and Leclerc I, Mol Cell Endocrinol. 2009 Jan 15;297(1-2):41-9. 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Epub 2011 Oct 17.' - id: RGD:7794795 citation: 'Xiao B, etal., Nature. 2011 Apr 14;472(7342):230-3. doi: 10.1038/nature09932. Epub 2011 Mar 13.' - id: RGD:7794796 citation: 'Banko MR, etal., Mol Cell. 2011 Dec 23;44(6):878-92. doi: 10.1016/j.molcel.2011.11.005. Epub 2011 Dec 1.'