Premium
AMPK ‐ the fuel gauge of the eukaryotic cell
Author(s) -
Hardie David Grahame
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.114.1
Subject(s) - ampk , protein kinase a , microbiology and biotechnology , adenylate kinase , kinase , phosphorylation , amp activated protein kinase , dephosphorylation , chemistry , biology , biochemistry , phosphatase , enzyme
The AMP‐activated protein kinase (AMPK) is expressed in essentially all eukaryotic cells and acts as a sensor of cellular energy status. It is a heterotrimer comprised of catalytic alpha subunits and regulatory beta and gamma subunits, and is only active after phosphorylation at Thr‐172 within the kinase domain by upstream kinases. AMPK is activated whenever a metabolic stress causes a decrease in the cellular ATP:ADP ratio: because of the adenylate kinase reaction, this is always accompanied by a much larger increase in the AMP:ATP ratio. Binding of AMP to the gamma subunit of AMPK causes two effects that are antagonized by ATP: (i) it inhibits dephosphorylation of Thr‐172, causing a sensitive switch to the active, phosphorylated form; (ii) it allosterically activates the phosphorylated kinase. The major upstream kinase in most cells is the tumor suppressor LKB1. Since AMPK can cause an arrest of cell growth and the cell cycle, activation of AMPK may explain why LKB1 is a tumor suppressor, although LKB1 also acts upstream of a family of twelve AMPK‐related kinases. In some cell types (e.g. neurones, endothelial cells and T cells), AMPK is also activated by increases in cell calcium, which trigger phosphorylation of Thr‐172 by CaMKK‐beta. The beta subunit of AMPK in all eukaryotes contains a carbohydrate‐binding module (CBM) that in mammalian cells causes AMPK to associate with glycogen. Recent work from our laboratory suggests that the CBM is a regulatory domain that inhibits AMPK when the reserves of energy in the form of glycogen are high.