Systems Level Regulation of Cardiac Energy Fluxes Via Metabolic Cycles: Role of Creatine, Phosphotransfer Pathways, and AMPK Signaling - Systems Biology of Metabolic and Signaling Networks - page 285

STK11). LKB1 is upstream of an entire family of 12 other AMPK-related kinases in
the human kinome, and like AMPK forms heterotrimers with two accessory
subunits, STRAD (Hawley et al. 2003 ; Woods et al. 2003 ).

LKB1 has originally been identified as a tumor suppressor whose inactivating
mutations lead to the Peutz-Jeghers syndrome, an inherited susceptibility to differ-
ent human cancers (Alessi et al. 2006 ). However, LKB1 seems to mostly exhibit
constitutive activity and may thus not be the limiting step in AMPK activation. An
alternative upstream kinase much less expressed in heart is Ca 2+ /calmodulin-
dependent protein kinase kinase β (CamKK β ) that mediates Ca 2+ -dependent
AMPK activation (Hawley et al. 2005 ; Hurley et al. 2005 ; Woods et al. 2005 ).
Although such CamKK

α / β and MO25 α / β

-mediated AMPK activation might anticipate an increas-
ing energy turnover that accompanies a rise in cytosolic Ca 2+

β

during muscle

contraction, its role in the heart is not well understood. More recently, the

transforming growth factor- -activated kinase-1 (TAK1) that phosphorylates the

yeast AMPK homologue Snf1 was proposed as an AMPK upstream kinase
(Momcilovic et al. 2006 ; Xie et al. 2006a ). Although TAK-1 is present in heart, it
is not activated during ischemia and it is unclear whether it acts via direct AMPK
phosphorylation (Xie et al. 2006a ).
Protein phosphatases are possibly the more critical parameter governing the

β

α -Thr172 phosphorylation state, and this may also apply to the heart. However,

their identity and regulatory role in vivo remain to be confirmed. Both seem to
depend on cell type and/or stimulus. Different phosphatases can act on AMPK,
including PP1, PP2A, and PP2C in vitro (Davies et al. 1995 ), as well as PP1-R6 in
MIN6 beta cells (Garcia-Haro et al. 2010 ) and metal-dependent phosphatase
PPM1E/F in HEK-293 cells in vivo (Voss et al. 2011 ). In heart and endothelial
cells, expression levels PP2C and 2A, respectively, correlate with AMPK activation
(Wang and Unger 2005 ; Wu et al. 2007 ).
The

α

-Thr172 phosphorylation state is further negatively controlled by hierar-
chical phosphorylation at other sites in the AMPK heterotrimer. Phosphorylation at
α

-Thr172
phosphorylation (Hurley et al. 2006 ; Horman et al. 2006 ; Djouder et al. 2010 ).
Further phosphorylation sites were identified in both α - and β -subunits, many of
them targeted by autophosphorylation, but their functional role remains uncertain.

1-Ser485 ( α 2-Ser491) by PKA or at α -Ser173 by PKB/Akt reduces α

11.5.4.2 Non-Covalent Allosteric Regulation by AMP and ADP

The activation of AMPK by low cellular energy state is triggered by increased
concentrations of AMP and, as discovered more recently, also of ADP, since the
kinase can sense AMP/ATP and ADP/ATP concentration ratios (Xiao et al. 2011 ;
Oakhill et al. 2011 ). In many cell types and in particular in heart, breakdown of ATP
to ADP at the onset of high workload or cellular stress has only minor immediate
effects on ATP levels. Due to the energy buffer and transfer function of the Cr/CK
system (see above), global and local ATP is rapidly replenished (Wallimann
et al. 2011 ; Neumann et al. 2003 ). Thus, ATP is not a very suitable signal for