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Page 4 of 16 Thirugnanam et al. Vessel Plus 2020;4:26 I http://dx.doi.org/10.20517/2574-1209.2020.18

referred to as “T-loop,” and is part of the three residues Leu (L)-Arg (R)-T that is conserved in the AMPK
protein family. An important step in LKB1 activation is its export from nucleus to the cytoplasm, and
this nuclear transport of LKB1 requires L-rich peptides. Kinases without a -2 L residue before the T-loop
residue cannot get phosphorylated or activated by LKB1 substrate. LKB1 possesses a strong preference to
[29]
phosphorylate T compared to the L residue at the -2 position in the T-loop. Interestingly, SNRK and the
13 other AMPK subfamily kinases that are phosphorylated and activated by LKB1 (AMPKα1, AMPKα2,
MARK1/2/3/4, SIK1/2/3, NUAK1/2, and BRSK1/2) has the L residue at the -2 position in the T-loop. LKB1
gets phosphorylated at S325, T366, and S431 residues by upstream kinases and is auto-phosphorylated at
[30]
S31, T185, T189, T336, and S404 residues. Interestingly, mutation in any of these phosphorylation sites
does not significantly affect its intracellular localization [31,32] .

LKB1 was originally identified as a mutated gene in the inherited Peutz-Jeghers Syndrome (PJS), in which
[33]
subjects are susceptible to developing benign and malignant tumors in the gastrointestinal organs
stomach and intestines. LKB1 protein is complexed with STE-related adapter (STRAD), an inactive
[35]
[34]
pseudokinase , and mouse protein 25 (MO25) , a repeat domain scaffold protein that is responsible
for activation of AMPK family kinases. Phosphorylation of S307 residue in LKB1 facilitates the binding
of LKB1 to the STRAD and MO25 complex, which enables the nucleocytoplasmic transport of LKB1-
complex [36,37] LKB1:STRAD:MO25 complex and Mg-ATP results in a rapid (20 min) 5-fold activation of
[11]
SNRK in the cytoplasm . Therefore, the heterotrimeric complex of LKB1, STRADα or STRADβ, and
MO25α or MO25β is required to obtain maximal activation of SNRK.

Role of SNRK in cardiomyocyte and adipocyte metabolism
To facilitate cell growth and maintenance, chemical reactions associated with cellular metabolism such as
glucose, fatty acid, and amino acid metabolism occurs within a cell. During periods of stress such as low
nutrient environment, the maintenance of cellular metabolism - in turn energy reserves in a cell - is critical.
AMPK is a key sensor of energy needs in a cell. SNRK like AMPK is beginning to show similar critical
roles in metabolism, and is observed in multiple tissues including adipose and cardiac tissues [13-19] . Central
to maintaining cellular energy homeostasis is the control of ATP generation and utilization. We discuss
next the emerging evidence regarding SNRK’s role in maintaining cellular energy homeostasis [Figure 2].

SNRK in cardiac metabolism
In the heart, the myocardium needs to function throughout the life of the organism. In the myocardium,
cardiomyocytes (CMs) are the powerhouses that generate energy. In the prenatal or in utero heart, glucose
and thus glycolysis is necessary for CMs growth. In late gestational and early postnatal stages, glucose
[38]
uptake is significantly decreased, creating an intracellular glucose deprivation during development . In
the late phase of cardiac fetal development, circulating lactate contributes to the majority of cardiac oxygen
consumption [39,40] while glucose and fatty acid oxidation (FAO) contribute relatively less [41,42] . In terms
of Snrk, during embryonic development, it is expressed at both mRNA and protein levels in tissues that
[19]
have high demand for metabolic activity . The heart is comprised of vascular endothelial cells (ECs) and
[15]
smooth muscle cells, in addition to CMs, all of which express SNRK . Loss of Snrk in all tissues [global
[15]
knockout (KO)] results in neonatal lethality with enlarged hearts observed at E17.5 and P0 . Microarray
[15]
analysis of E17.5 hearts revealed systemic metabolic dysregulation . Glycogen, a polysaccharide (serves
as glucose storage) was decreased in E17.5 Snrk global KO hearts. Similarly, lipid storage deposits
demonstrated by oil red O (ORO) staining was also less in E17.5 Snrk global KO heart tissue. Circulating
lipid plasma levels were also lower in Snrk global KO mice. Thus, global loss of Snrk results in defects
associated with cardiac tissue energy sources.

The phospho-AMPK-phospho-acetyl-CoA carboxylase (ACC) is one of the key signaling pathways
[15]
associated with cardiac metabolism in neonates and adults. AMPK decreases FAO by phosphorylation