• 목록
• 답변
• 글쓰기
• 게시판 리스트 옵션
  • 수정
  • 삭제

Talyzed by at least two upstream kinases: LKB1, which appears to be constitutively active, and CaMKK, which is only active when intracellular Ca2+ increases. Increases in AMP or ADP activate AMPK by three mechanisms: (1) binding of AMP or ADP to AMPK, causing a conformational change that promotes phosphorylation by upstream kinases (usually this will be LKB1, unless [Ca2+] is elevated); (2) binding of AMP or ADP, causing a conformational change that inhibits dephosphorylation by protein phosphatases; (3) binding of AMP (and not ADP), causing allosteric activation of AMPK-P. All three effects are antagonized by ATP, allowing AMPK PubMed ID:https://www.ncbi.nlm.nih.gov/pubmed/14445666 to act as an energy sensor.LKBNUAK1/ARK5 NUAK2/SNARK SIK1/SIKFigure 4. Members of the AMPK and AMPK-related kinase (ARK) family. All the kinases named in the figure are phosphorylated and activated by LKB1, although what regulates this phosphorylation is known only for AMPK. Alternative names are shown, where applicable.Hardie and Alessi BMC Biology 2013, 11:36 http://www.biomedcentral.com/1741-7007/11/Page 5 ofwhich appear to be involved in regulation of cell proliferation, and the SIKs, involved in the regulation of gluconeogenesis.The immediate aftermath (2): more kinases upstream of AMPK Our 2003 paper [1] showed that although genetic loss of LKB1 in mammalian cells greatly reduces phosphorylation of AMPK on Thr172, it does not eliminate it entirely, suggesting that other kinases must also phosphorylate the site. The DGH group had reported in 1995 that calmodulin-dependent kinase kinases (CaMKKs) could activate AMPK [27], although it was not clear at the time that this was physiologically relevant. However, DGH and others soon reported that CaMKKs (especially the CaMKK isoform) did indeed provide an alternative Ca2+-stimulated pathway by which AMPK could be activated in intact cells in the absence of LKB1 [36-38]. This pathway accounts for AMPK activation in neurones exposed to membrane depolarization [36], in T cells activated via the antigen receptor [39], and in cells treated with ligands for G protein-coupled receptors that trigger intracellular release of inositol trisphosphate and hence Ca2+. The latter include endothelial cells treated with thrombin [40], and hypothalamic neurones involved in appetite control treated with the `hunger hormone' ghrelin [41,42]. Interestingly, despite the very close sequence similarities within the activation loops of AMPK and the ARKs, none of the ARKs appear to be phosphorylated and activated by CaMKK [43]. New findings arising from genetic ablation of LKB1 Null mutations of either LKB1 or AMPK are embryonic lethal in mice, which means that conditional knockouts are necessary to study their function in vivo. This is, however, complicated in the case of AMPK by the existence of two or three functionally redundant isoforms of each of the three subunits, so that genes encoding all isoforms of one subunit must be knocked out to produce a phenotype. The identification of LKB1 as the upstream kinase 3-(2,4-Dichlorophenoxy)azetidine activating AMPK simplified the investigation of AMPK function in vivo, because LKB1 is encoded by a single gene. It allowed the demonstration, 3-Dimethyl-2-(2 for example, that mice with a muscle-specific knockout of LKB1, in PubMed ID:https://www.ncbi.nlm.nih.gov/pubmed/14445666 which AMPK was no longer activated by contraction, failed to display the normal increase in muscle glucose uptake in response to contraction [44]. 4-((2-Hydroxyethyl)(methyl)amino)benzaldehyde The convenience of having to knock out only a single gene is counterbalanced, however, by the status of LKB1 as a master upstre.