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


CONCLUSIONS
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.
Kimura
Naoki
N
Biosignal Research Center, Kobe University, Kobe 657-8501, Japan.
Tokunaga
Chiharu
C
Dalal
Sushila
S
Richardson
Christine
C
Yoshino
Ken-ichi
K
Hara
Kenta
K
Kemp
Bruce E
BE
Witters
Lee A
LA
Mimura
Osamu
O
Yonezawa
Kazuyoshi
K
D055372:AMP-Activated Protein Kinases; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D004347:Drug Interactions; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology; D009097:Multienzyme Complexes / Q000502:physiology*; D010766:Phosphorylation; D011494:Protein Kinases / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D012265:Ribonucleotides / Q000494:pharmacology; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases; D014407:Tumor Cells, Cultured
D007004:Hypoglycemic Agents; D007328:Insulin; D009097:Multienzyme Complexes; D011518:Proto-Oncogene Proteins; D012265:Ribonucleotides; D000620:Aminoimidazole Carboxamide; D011494:Protein Kinases; C546842:MTOR protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; C031143:AICA ribonucleotide