A possible linkage between AMP‐activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) signalling pathway

• Published in: Genes to cells : devoted to molecular & cellular mechanisms 2003-01, Vol.8 (1), p.65-79
• Main Authors: Kimura, Naoki, Tokunaga, Chiharu, Dalal, Sushila, Richardson, Christine, Yoshino, Ken‐ichi, Hara, Kenta, Kemp, Bruce E., Witters, Lee A., Mimura, Osamu, Yonezawa, Kazuyoshi
• Format: Article
• Language: English
• Subjects: Aminoimidazole Carboxamide - analogs & derivatives; Aminoimidazole Carboxamide - pharmacology; AMP-Activated Protein Kinases; Drug Interactions; Humans; Hypoglycemic Agents - pharmacology; Insulin - pharmacology; Multienzyme Complexes - physiology; Phosphorylation; Protein Kinases - physiology; Protein-Serine-Threonine Kinases - physiology; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-akt; Ribonucleotides - pharmacology; Ribosomal Protein S6 Kinases, 70-kDa - antagonists & inhibitors; Ribosomal Protein S6 Kinases, 70-kDa - metabolism; Signal Transduction - drug effects; Signal Transduction - physiology; TOR Serine-Threonine Kinases; Tumor Cells, Cultured
• ISSN: 1356-9597; 1365-2443
• DOI: 10.1046/j.1365-2443.2003.00615.x

Background: The mammalian target of rapamycin (mTOR) regulates multiple cellular functions including translation in response to nutrients, especially amino acids. AMP‐activated protein kinase (AMPK) modulates metabolism in response to energy demand by responding to changes in AMP. Results: The treatment of SV40‐immortalized human corneal epithelial cells (HCE‐T cells) with 5‐aminoimidazole‐4‐carboxamide ribonucleoside (AICAR), widely used as an AMPK activator, inhibits p70 S6k activities. Altered glucose availability, which regulates AMPK activity, also modulates the activity of p70 S6k. AICAR treatment also inhibits phosphorylation of Thr‐412 in the p70 S6 kinase (p70 S6k), which is indispensable for the activity. Furthermore, over‐expression of mutant AMPK subunits by stable expression in rabbit pulmonary fibroblast cell lines (PS120 cells) also modulates p70 S6k activity. The insensitivity of the rapamycin‐resistant p70 S6k variant to AICAR treatment suggests that the inhibition of p70 S6k is mediated through a common effector, supporting a model whereby mTOR and its downstream effector are controlled by AMPK. Conclusion: These results indicate that the AMPK and mTOR signalling pathways are possibly linked. In addition to the mTOR signal acting as a priming switch that modulates p70 S6k activation, AMPK appears to provide an overriding switch linking p70 S6k regulation to cellular energy metabolism.