Localization of AMP kinase is regulated by stress, cell density, and signaling through the MEK-->ERK1/2 pathway.
5'-AMP-activated protein kinase (AMPK) serves as an energy sensor and is at the center of control for a large number of metabolic reactions, thereby playing a crucial role in Type 2 diabetes and other human diseases. AMPK is present in the nucleus and cytoplasm; however, the mechanisms that regulate the intracellular localization of AMPK are poorly understood. We have now identified several factors that control the distribution of AMPK. Environmental stress regulates the intracellular localization of AMPK, and upon recovery from heat shock or oxidant exposure AMPK accumulates in the nuclei. We show that under normal growth conditions AMPK shuttles between the nucleus and the cytoplasm, a process that depends on the nuclear exporter Crm1. However, nucleocytoplasmic shuttling does not take place in high-density cell cultures, for which AMPK is confined to the cytoplasm. Furthermore, we demonstrate that signaling through the mitogen-activated protein kinase kinase (MEK)-->extracellular signal-regulated kinase 1/2 (ERK1/2) cascade plays a crucial role in controlling the proper localization of AMPK. As such, pharmacological inhibitors that interfere with this pathway alter AMPK distribution under nonstress conditions. Taken together, our studies identify novel links between the physiological state of the cell, the activation of MEK-->ERK1/2 signaling, and the nucleocytoplasmic distribution of AMPK. This sets the stage to develop new strategies to regulate the intracellular localization of AMPK and thereby the modification of targets that are relevant to human disease.
Kodiha
Mohamed
M
Department of Physiology, McGill University, Montreal H3G 1Y6, Canada.
Rassi
James G
JG
Brown
Claire M
CM
Stochaj
Ursula
U
D021581:Active Transport, Cell Nucleus; D000263:Adenylate Kinase / Q000737:chemistry / Q000378:metabolism*; D002452:Cell Count; D002467:Cell Nucleus / Q000201:enzymology / Q000378:metabolism*; D003593:Cytoplasm / Q000201:enzymology / Q000378:metabolism*; D005419:Flavonoids / Q000494:pharmacology; D006367:HeLa Cells; D006358:Hot Temperature; D006801:Humans; D028884:Karyopherins / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018384:Oxidative Stress; D010455:Peptides / Q000494:pharmacology; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D044967:Serum / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013312:Stress, Physiological / Q000201:enzymology / Q000378:metabolism*; D013912:Threonine / Q000737:chemistry; D013997:Time Factors; D000097606:Exportin 1 Protein
D000263:Adenylate Kinase; D005419:Flavonoids; D028884:Karyopherins; D020930:MAP Kinase Kinase Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D010455:Peptides; D047428:Protein Kinase Inhibitors; D018160:Receptors, Cytoplasmic and Nuclear; D013912:Threonine; D000097606:Exportin 1 Protein; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one