Adenylate Kinase Isoform Network: A Major Hub in Cell Energetics and Metabolic Signaling - Systems Biology of Metabolic and Signaling Networks - page 145

The minor AK6 isoform, also known as transcription factor TAF9 and hCINAP,
is localized in the cell nucleus along with AK5 which associates with centrosomes;
both isoforms are required for cell growth (Noma 2005 ; Ren et al. 2005 ;Zhai
et al. 2006 ). Human AK5 was identified to have two enzymatically active adenylate
kinase domains which could catalyze sequential phosphoryl transfer (Solaroli
et al. 2009 ). Another isoform, AK7, has a tissue-specific expression pattern and
its activity has been associated with cilia function (Fernandez-Gonzalez
et al. 2009 ). The next AK8 isoform is the second known human adenylate kinase
with two complete and active catalytic domains within its polypeptide chain, a
feature that previously was shown also for AK5 (Panayiotou et al. 2011 ). AK8 has
nuclear, nucleoli, and mitochondrial localization (see http://www.proteinatlas.org/
ENSG00000165695 ) . Both AK7 and the full length AK8 have high affinity for
AMP and are more efficient in AMP phosphorylation as compared to the major
cytosolic isoform AK1 (Panayiotou et al. 2011 ). This property may be advanta-
geous for energetic circuits supporting ciliary motility and cell migration (Dzeja
and Terzic 1998 ). Recently, a new member of the adenylate kinase family has been
identified and named AK9 (Amiri et al. 2013 ). This isoform has both cytosolic and
nuclear localization and its significance remains to be determined. Also, the exact
substrate specificity of the AK9 needs to be resolved with pure enzyme preparations
(Amiri et al. 2013 ).
The significance of the adenylate kinase isoform network and AMP signaling is
highlighted by recent studies indicating that mutations in AK1, AK2, and AK7
genes are associated with severe human disease and that AK1 and AK2 isoforms are
critical in stem cell differentiation as well as for unfolded protein stress response
(Burkart et al. 2010 ; Dzeja et al. 2011a ; Fernandez-Gonzalez et al. 2009 ; Inouye
et al. 1998 ; Lagresle-Peyrou et al. 2009 ; Pannicke et al. 2009 ). Protein knockdown
using siRNAs indicates that AK1, AK2, and AK5 isoforms are involved in
cardiomyocyte differentiation, mitochondrial biogenesis, and network formation
and for development of cardiac beating area and contractile performance (Dzeja
et al. 2011a ). Deficiency of AK2, which is localized to the mitochondrial inter-
membrane space at crossroads of high-energy phosphoryl flux, arrests
hematopoietic stem cell differentiation in humans (Lagresle-Peyrou et al. 2009 ;
Pannicke et al. 2009 ) and is embryonically lethal in Drosophila and mice (Fujisawa
et al. 2009 ; Noma 2005 ; Zhang et al. 2010b ). Absence or reduction of AK2 protein
would interfere with mitochondrial bioenergetics and mitochondria-nucleus ener-
getic communication that could compromise implementation of the leukocyte
developmental program (Lagresle-Peyrou et al. 2009 ; Pannicke et al. 2009 ). Indeed,
preliminary data indicate that AK2 mouse embryonic fibroblasts (MEFs) have

severely disrupted mitochondrial cristae structure, and display low growth and
proliferation potential (Zhang et al. 2010b ). Ak2 deficiency could compromise
evolvement of the mitochondrial network and establishment of metabolic circuits
that are part of developmental programming and execution of cell differentiation
sequences (Chung et al. 2007 , 2008 , 2010 ; Dzeja et al. 2011a ). Indeed, AK2
regulates cell growth, viability, and proliferation in insect growth and development
(Chen et al. 2012 ). Moreover,

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it was discovered that adenylate kinase and