Regulation by subcellular localization

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Intracellular distribution of AMPK complexes appears to shuttle between the nucleus and the cytoplasm in response to specific stimuli. In Hela cells, AMPK translocated to the nucleus upon stimulation by agents inducing cellular stress (Kodiha et al., 2007). In human skeletal muscle, the AMPKa2 subunit translocated to the nucleus following intense exercise (McGee et al., 2003). Interestingly, the two AMPKa subunits, a1 and a2, have been shown to have different localization patterns in mammalian cells, with the a1 subunit being localized to the non-nuclear fraction and the a2 subunit localized to both the nucleus and the non-nuclear fractions. AMPKa1 is hence likely to phosphorylate cytosolic and plasma membrane substrates, whereas AMPKa2 may be primarily involved in the conversion of metabolic signals into transcriptional regulation (Salt et al., 1998a). Another mechanism to localize signaling events is the association with scaffold proteins. The b subunits act as targeting scaffolds, influencing subcellular localization through an N-terminal myristoylation site (Mitchelhill et al., 1997) that can target AMPK to membrane (Gregor et al., 2006; Warden et al., 2001). AMPKa2 bound to AMPKb1 is anchored in the cytoplasm at the outer mitochondrial membrane through the myristoylation site of b1 subunit. In contrast, AMPKa2 bound to AMPKb2 translocates to the nucleus in a manner driven by a nuclear localization signal present in AMPKa2 but not in AMPKa1 subunit (Suzuki et al., 2007). The g1 subunit also exhibits preferential nuclear localization over the other g subunits (Turnley et al., 1999). These data suggest that activation of AMPK complexes may elicit distinct metabolic as well as signaling effects in tissues and cells depending on the expression of different catalytic and regulatory subunits.