Adenylate Kinase Isoform Network: A Major Hub in Cell Energetics and Metabolic Signaling - Systems Biology of Metabolic and Signaling Networks - page 148

et al. 2010 ). The regulation of these processes is central for maintaining tissue
homeostasis, whereas dysregulation may lead to diseases such as cancer, diabetes,
and neurodegenerative disorders (Dzeja and Terzic 2009 ; Motoshima et al. 2006 ). It
has been suggested that dynamics of nuclear-cytosolic protein localization,
phosphorelays of energetic and signaling cascades, and spatially and temporally
controlled proteolysis with protein modification events are overlayed on the net-
work that controls cell cycle progression and differentiation (Domian et al. 1997 ;
Ptacin and Shapiro 2013 ).
Phosphotransfer enzyme adenylate kinase facilitates mitochondrial-nuclear
energetic communication (Dzeja et al. 2002 ) and within the nucleus, embedded
into organized enzymatic complexes of nucleotide-metabolizing and
phosphotransfer enzymes, is involved in maintaining proper nuclear dNTP ratios
and facilitates channeling of nucleotides into DNA replication machinery (Kim
et al. 2005 ). Imbalances in dNTP ratios affect the fidelity of DNA replication and
repair leading to acquired mutations (Dzeja and Terzic 2007 ; Kim et al. 2005 ). In
yeast AK(Adk1p) is bound to chromatin throughout the cell cycle, physically
interacts with pre-replicative complexes, including Orc3p and Cdc14p proteins,
and is required for DNA replication initiation and cell cycle control (Cheng
et al. 2011 ). Thus, adenylate kinase in the nucleus surveys nucleotide ratios
necessary for error-free DNA replication, while another nuclear protein Rad50,
harboring or having associated adenylate kinase activity, participates in DNA
double-strand break repair (Bhaskara et al. 2007 ). As AK1 has no known nuclear
localization sequence, the molecular mechanisms of AK translocation to the
nucleus are still obscure (Strobel et al. 2002 ).
In recent years, nuclear adenylate kinase isoforms have been characterized in
several organisms, such as Drosophila melanogaster (Meng et al. 2008 ), Saccha-
romyces cereviciae (FAP7) (Juhnke et al. 2000 ), Caenorhabditis elegans (Zhai
et al. 2006 ), and Homo sapiens (hCINAP) (Malekkou et al. 2010 ; Ren et al. 2005 ).
Moreover, the human isoform (hCINAP) is involved in Cajal body organization,
gene transcription, and cell cycle progression (Santama et al. 2005 ; Zhang
et al. 2010a ). Recent study of nuclear shuttling of adenylate kinase in Trypanosoma
cruzi (TcADKn) has identified its noncanonical nuclear localization signal, being
one of the few atypical NLS that involves the catalytic site of the protein (Walker
domain or P-loop) (Camara Mde et al. 2013 ). It is postulated that TcADKn enters
the nucleus in an unfolded conformation, being the nuclear localization signal
within the P-loop, and once it enters the nucleus, it folds correctly regarding the
active site inside the protein. TcADKn could be forming a complex with other
proteins, which are recognized by the importin and then enters the nucleus, or it
could be recognized directly by the importing complex (Camara Mde et al. 2013 ).
TcADKn nuclear export depends on the nuclear exportation adapter CRM1, and its
nuclear shuttling is regulated by nutrient availability, ribosome biogenesis, DNA
integrity, and oxidative stress. Posttranslational modification of AK isoforms (acet-
ylation, myristoylation, glutathionylation, and S-nitrosylation) can play a role in
directing AK to nuclear and other compartments, according to local energetic needs