[PDF][PDF] Ca2+/calmodulin-dependent protein kinase kinase-β acts upstream of AMP-activated protein kinase in mammalian cells

A Woods, K Dickerson, R Heath, SP Hong… - Cell metabolism, 2005 - cell.com
A Woods, K Dickerson, R Heath, SP Hong, M Momcilovic, SR Johnstone, M Carlson…
Cell metabolism, 2005cell.com
AMP-activated protein kinase (AMPK) is the downstream component of a kinase cascade
that plays a pivotal role in energy homeostasis. Activation of AMPK requires phosphorylation
of threonine 172 (T172) within the T loop region of the catalytic α subunit. Recently, LKB1
was shown to activate AMPK. Here we show that AMPK is also activated by Ca
2+/calmodulin-dependent protein kinase kinase (CaMKK). Overexpression of CaMKKβ in
mammalian cells increases AMPK activity, whereas pharmacological inhibition of CaMKK, or …
Summary
AMP-activated protein kinase (AMPK) is the downstream component of a kinase cascade that plays a pivotal role in energy homeostasis. Activation of AMPK requires phosphorylation of threonine 172 (T172) within the T loop region of the catalytic α subunit. Recently, LKB1 was shown to activate AMPK. Here we show that AMPK is also activated by Ca2+/calmodulin-dependent protein kinase kinase (CaMKK). Overexpression of CaMKKβ in mammalian cells increases AMPK activity, whereas pharmacological inhibition of CaMKK, or downregulation of CaMKKβ using RNA interference, almost completely abolishes AMPK activation. CaMKKβ isolated from rat brain or expressed in E. coli phosphorylates and activates AMPK in vitro. In yeast, CaMKKβ expression rescues a mutant strain lacking the three kinases upstream of Snf1, the yeast homolog of AMPK. These results demonstrate that AMPK is regulated by at least two upstream kinases and suggest that AMPK may play a role in Ca2+-mediated signal transduction pathways.
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