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AMP-activated protein kinase (AMPK) is a member of a family of serine-threonine protein kinases which are found in all eukaryotes. The unique ability of AMPK to directly sense the energy status of the cell makes it an attractive target molecule for ensuring that cell division proceeds when cells have sufficient metabolic resources to support cell proliferation. AMPK is also an antigrowth molecule due to its relationship to two tumor suppressor genes: LKB1 and TSC2. LKB1 is the upstream activating kinase for the stress-responsive AMP-activated kinase and links regulators of cellular metabolism and cell proliferation in cancer. LKB1 activates AMPK and thus acts as the principal AMPKK. LKB1 also protects cells from apoptosis in response to agents that elevate intracellular AMP. Embryonic fibroblasts of LKB1-deficient mice are defective in AMPK activation and undergo apoptosis under conditions that elevate AMP. Ca2+/calmodulin-dependent protein kinase also regulates AMPK in cell lines that lack LKB1 expression.
AMPK activity requires phosphorylation of the R subunit on Thr-172 in its activation loop by one or more upstream kinases (AMPKK). AMPK phosphorylation down-regulates ATP-consuming processes, such as the synthesis of proteins, fatty acids and cholesterol, and while up-regulating ATP-producing catabolic pathways, such as glucose uptake and fatty acid oxidation. In addition, AMPK activation regulates apoptosis in multiple types of cancer cells by signaling pathways, such as Akt, COX-2, and mTOR, which include the up-regulation of p21 and p53 proteins, activation of caspases, inhibition of molecules related to growth, and proliferation of cancer cells.
Figure 1. AMPK signaling pathway.
As a cellular energy regulator, AMPK plays an important role in glucose metabolism in many metabolic disorders such as diabetes, and it has emerged as a promising therapeutic target for the treatment of these metabolic disorders. AMPK activation promotes glucose uptake and translocation of GLUT4 in skeletal muscle in type 2 diabetes, and reduces hepatic gluconeogenesis by directly attenuating the expression of G6Pase and PEPCK. The activation of AMPK owing to muscle contraction and hypoxia increased ACC-β phosphorylation, which then inhibited ACC activity and consequently reduced malonyl-CoA content, increasing carnitine palmitoyltransferase 1 activity and increased fatty-acid oxidation.
With a more complete list of AMPK substrates, it is becoming clear that there is a convergence of AMPK signaling with Erk and PI3K signaling in growth control pathways, and with insulin and cAMP-dependent pathways in metabolic control. Furthermore, as more targets of AMPK are decoded, the challenge will be in defining more precisely which targets are indispensable and relevant for the beneficial effects of AMPK activation seen in pathological states ranging from diabetes to neurological disorders to cancer. The identification of downstream effectors will provide new targets for therapeutically treating these diseases through unlocking this endogenous mechanism that evolution has developed to restore cellular and organismal homeostasis. Creative Biogene can offer a variety of AMPK signaling pathway related products including stable cell lines, viral particles and clones for your drug discovery projects.
AMPK Signaling Pathway Product Panel
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