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Fig. 6.2 Adenylate kinase provides energy and metabolic signaling for cell division cycle.
Adenylate kinase translocates to the cell nucleus and associates with the mitotic spindle during
cell division cycle (Dzeja et al. 2011a ). Such adenylate kinase redistribution is advantageous for
delivery and on-site regeneration of ATP, thus furnishing high energy needs of mitotic spindle
movements required for chromosome disjunction and completion of cell division cycle through
cytokinesis. AK adenylate kinase
myosin-9, tubulin, TEM1, DUO1, CBL2, PHO85, IPL1, MAD2, and others. In this
regard, the AK2 isoform, which when mutated causes leukocyte developmental
arrest, in yeasts interacts with DUO1, a component of Dam1 complex, and with a
network regulating cell cycle including IPL1 (Aurora kinase subunit), MAD2,
NAP1, SLJ15, STU2, and others (Tarassov et al. 2008 ).
The
second AK1
gene
product,
the
p53-inducible membrane-bound
myristoylated AK1
isoform, is implicated in p53-dependent cell cycle arrest and
nucleotide exchange in the submembrane space (Collavin et al. 1999 ; Janssen
et al. 2004 ; Ruan et al. 2002 ). Since gene encoding AK1 is downregulated during
tumor development, it could result in lower AK1
β
β
levels and cell cycle disturbances
β
(Vasseur et al. 2005 ). AK1
also associates with the nuclear envelope (Janssen
et al. 2004 ) and epithelium microvilli (Bonilha et al. 2004 ), suggesting a role in
energy support of nuclear and epithelia transport processes.
Developmental deployment and upregulation of the adenylate kinase/AMPK
signaling axis provides a nucleo-cytosolic energetic and metabolic signaling vector
integral to execution of stem cell cardiac differentiation (Dzeja et al. 2011a ). Other
studies indicate that adenylate kinase isoforms in the brain may contribute to
neuronal maturation and regeneration (Inouye et al. 1998 ; Yoneda et al. 1998 ).
Thus, targeted redistribution of the adenylate kinase-AMPK circuit associated with
cell cycle and asymmetric cell division uncovers a new regulator for cardiogenesis
and heart tissue regeneration.
Recently, using metabolomic technologies, we have discovered that in adult
hearts increased expression of adenylate kinase isoforms (AK1, AK2, and AK1
)
and high energy and AMP signal dynamics, measured by 18 O-labeling, is misread
by AMPK as a “low energy” state, inducing blockade of cell cycle metabolic
checkpoint and cardiomyocyte proliferation and renewal (Mandal et al. 2005 ;
Zhang et al. 2012 ). Similarly, an excess AMP signaling in the periphery, induced
β
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