Abstract
As the central node between nutrition signaling input and the metabolic pathway, AMP-activated protein kinase (AMPK) is tightly regulated to maintain energy homeostasis. Subcellular compartmentalization of AMPK is one of the critical regulations that enables AMPK to access proper targets and generate appropriate responses to specific perturbations and different levels of stress. One of the characterized localization mechanisms is RanGTPase-driven CRM1 that recognizes the nuclear export sequence (NES) on the α subunit to translocate AMPK into the cytoplasm. Nuclear localization putatively employs RanGTPase-driven importin that might recognize the nuclear localization signal (NLS) present on the AMPKα2 kinase domain. Nucleo-cytoplasmic shuttling of AMPK is influenced by multiple factors, such as starvation, exercise, heat shock, oxidant, cell density, and circadian rhythm. Tissue-specific localization, which distributes AMPK trimers with different combinations, has also been shown to be vital in maintaining tissue-specific metabolism. Tissue-specific and subcellular distribution of AMPK might be attributed to differences in the expression of the subunit, the stabilization by protein regulators, tissue activity, and the localization of AMPK activators. Considering the importance of AMPK localization in coordinating signaling and metabolism, further research is due to fully elucidate the largely unknown complex mechanism underlying this regulation.
Highlights
AMPactivated protein kinase (AMPK) is highly regulated by upstream kinases including liver kinase B1 (LKB1) in a nucleotide-dependent pathway, and calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2) in a nucleotide-independent pathway [3,4]
Recent studies reported that TGF-beta-activated kinase 1 (TAK1) and A-T mutated protein (ATM) can act as AMPK kinases [5,6]
AMPKα is essential for cytoplasmic and nuclear localization as the subunit contains sequences recognized by nuclear transport receptors (NTRs) for subsequent transport
Summary
Nutrient availability serves as a metabolic input to regulate gene and protein expression, as well as protein activity. AMP-activated protein kinase (AMPK) is a highly conserved serine/threonine kinase that links nutrient input to metabolic pathways to regulate energy homeostasis [1]. AMPK orthologs are present is almost all eukaryotes, serving a central role in regulating adaptive responses to starvation. In higher eukaryotes, such as mammals, AMPK is utilized to regulate growth and metabolism in whole body as well as in specific tissues. LKB1 is involved in AMPK regulation when the AMP level rises due to starvation, exercise, ischemia, and mitochondrial inhibitors, while. AMPK activation will promote catabolic reaction including glycolysis, fatty acid oxidation, glucose uptake, autophagy, mitophagy, and mitochondrial fission to increase ATP levels [2]. AMPK can inhibit anabolic reactions that utilize ATP, such as the synthesis of protein, fatty acid, sterol, glycogen, and rRNA [2]
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