DYRK1A: the double-edged kinase as a protagonist in cell growth and tumorigenesis

Abstract

DYRK1A (dual-specificity tyrosine-regulated kinase 1A) is a kinase with multiple implications for embryonic development, especially in the nervous system where it regulates the balance between proliferation and differentiation of neural progenitors. The DYRK1A gene is located in the Down syndrome critical region and may play a significant role in the developmental brain defects, early neurodegeneration, and cancer susceptibility of individuals with this syndrome. DYRK1A is also expressed in adults, where it might participate in the regulation of cell cycle, survival, and tumorigenesis, thus representing a potential therapeutic target for certain types of cancer. However, the final readout of DYRK1A overexpression or inhibition depends strongly on the cellular context, as it has both tumor suppressor and oncogenic activities. Here, we will discuss the functions and substrates of DYRK1A associated with the control of cell growth and tumorigenesis with a focus on the potential use of DYRK1A inhibitors in cancer therapy.

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DYRK1A: the double-edged kinase as a protagonist in
cell growth and tumorigenesis
P Fernández-Martíneza, C Zahonerob & P Sánchez-Gómezb
a Instituto de Medicina Molecular Aplicada; Universidad CEU-San Pablo; Madrid, Spain
b Neuro-oncology Unit; Instituto de Salud Carlos III-UFIEC; Madrid, Spain
Published online: 30 Jan 2015.
To cite this article: P Fernández-Martínez, C Zahonero & P Sánchez-Gómez (2015) DYRK1A: the double-edged
kinase as a protagonist in cell growth and tumorigenesis, Molecular & Cellular Oncology, 2:1, e970048, DOI:
10.4161/23723548.2014.970048
To link to this article: http://dx.doi.org/10.4161/23723548.2014.970048
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DYRK1A: the double-edged kinase as a
protagonist in cell growth and tumorigenesis
P Fern
andez-Martínez
1
, C Zahonero
2
, and P S
anchez-G
omez
2,
*
1
Instituto de Medicina Molecular Aplicada; Universidad CEU-San Pablo; Madrid, Spain;
2
Neuro-oncology Unit; Instituto de Salud Carlos III-UFIEC; Madrid, Spain
Keywords: cancer, cell proliferation, cell differentiation, DYRK1A, neural progenitors
DYRK1A (dual-specificity tyrosine-regulated kinase 1A) is a
kinase with multiple implications for embryonic
development, especially in the nervous system where it
regulates the balance between proliferation and
differentiation of neural progenitors. The DYRK1A gene is
located in the Down syndrome critical region and may play a
significant role in the developmental brain defects, early
neurodegeneration, and cancer susceptibility of individuals
with this syndrome. DYRK1A is also expressed in adults, where
it might participate in the regulation of cell cycle, survival,
and tumorigenesis, thus representing a potential therapeutic
target for certain types of cancer. However, the final readout
of DYRK1A overexpression or inhibition depends strongly on
the cellular context, as it has both tumor suppressor and
oncogenic activities. Here, we will discuss the functions and
substrates of DYRK1A associated with the control of cell
growth and tumorigenesis with a focus on the potential use
of DYRK1A inhibitors in cancer therapy.
Introduction
DYRK (dual-specificity tyrosine-regulated kinase) family
members represent a subfamily of protein kinases that have been
identified in distantly related organisms such as yeast, Drosophila,
and human. Seven mammalian Dyrk-related kinases have been
identified: DYRK1A, DYRK1B, DYRK1C, DYRK2, DYRK3,
DYRK4A, and DYRK4B.
1,2
The DYRK proteins are dual-speci-
ficity protein kinases that autophosphorylate a conserved tyrosine
(Y) residue in their own activation loop but phosphorylate their
substrates at serine (S) or threonine (T) residues.
3,4
The Y auto-
phosphorylation occurs during translation and induces kinase
activation; however, once the protein is fully translated, kinase
activity becomes restricted to S and T residues and no longer
depends on Y phosphorylation.
5,6
DYRK1A is the most extensively studied among this family of
kinases because its gene maps to human chromosome 21 within
the Down syndrome critical region (DSCR).
7-9
Moreover, this
kinase is overexpressed in the brain of patients with Down syn-
drome (DS) and many of its known substrates have been linked
to neuropathologic traits of this syndrome.
10,11
In fact, accumu-
lating evidence in experimental models suggests that DYRK1A
inhibitors can reverse some of the neurologic alterations associ-
ated with its overexpression and therefore could be of use in indi-
viduals with DS.
12
These aspects have been extensively reviewed
elsewhere. However, there are other less well-known facets of
DYRK1A, such as its participation in cancer. Many of its down-
stream targets are associated with the control of cell growth and
survival, especially in the nervous system, where it has been
mostly studied, but also in other tissues. Interestingly, in the can-
cer context, DYRK1A activity might be linked to both oncogene-
sis and tumor suppression. Here, we will try to summarize all
known implications of DYRK1A function in cell growth and
cancer with the aim of understanding this dichotomy, which
could have clinically relevant implications for the development of
therapeutic DYRK1A inhibitors.
Role of DYRK1A in Embryonic and Adult
Neurogenesis
Vertebrate Dyrk1A is expressed ubiquitously in a broad spec-
trum of embryonic tissues at different stages of development but
also in some adult tissues, most prevalently in heart, lung, brain,
and skeletal muscle.
7-9,13
In mice, the absence of Dyrk1A is lethal
at the embryonic stage. Heterozygous animals are viable but have
a reduced size at birth that is maintained through adulthood. This
reduction is more noticeable in organs such as the brain and liver.
Heterozygous mice show decreased neonatal viability, a reduced
number of neurons in brain areas, alterations in motor and devel-
opment, dopaminergic deficiency, and impairment in spatial learn-
ing development.
14,15
Conversely, transgenic mice overexpressing
Dyrk1A also present a neurodevelopmental delay and motor and
cognitive deficits.
16-18
These data reflect the extreme gene dosage
sensitivity of this protein and its relevance during neural system
(NS) development, where it controls proliferation, neurogenesis,
neural differentiation, cell death, and synaptic plasticity.
19,20
Drosophila Dyrk1A mutants (minibrain, mnb
-/-
flies) develop a
smaller adult brain (especially the optic lobes and the central brain
hemispheres), which appears to be caused by altered neuroblast
© P Fern
andez-Martínez, C Zahonero, and P S
anchez-G
omez
*Correspondence to: P S
anchez-G
omez; Email: psanchezg@isciii.es
Submitted: 06/13/2014; Revised: 09/03/2014; Accepted: 09/03/2014
http://dx.doi.org/10.4161/23723548.2014.970048
This is an Open Access article distributed under the terms of the Creative
Commons Attribution-Non-Commercial License (http://creativecommons.
org/licenses/by-nc/3.0/), which permits unrestricted non-commercial use,
distribution, and reproduction in any medium, provided the original work is
properly cited. The moral rights of the named author(s) have been asserted.
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proliferation during postembryonic neurogenesis.
21
Interestingly,
recent evidence suggests that this function is not restricted to the
NS as Mnb is also required for normal leg and wing growth con-
trol.
22
Moreover, truncation of the human DYRK1A gene causes
microcephaly,
23
further supporting an evolutionary conserved
function of this kinase during brain development. There appears to
be a dynamic spatiotemporal expression pattern of Dyrk1A that is
tightly controlled during vertebrate NS development. There is a
transient peak of expression of mouse Dyrk1A immediately before
the transition from proliferating to neurogenic divisions.
24
After
that, its expression is maintained in neural progenitors (NPs),
although at a lower level. Later on, Dyrk1A is upregulated in new-
born postmitotic neurons and downregulated as the neuron begins
to migrate away from the ventricular zone. Once the migrating neu-
ron reaches its target position, Dyrk1A is again expressed before the
final differentiation and dendrite formation occurs.
25,26
These
changes in Dyrk1A expression reinforce the notion that it works as
an inhibitor of cell cycle progression. In fact, in utero electropora-
tion of Dyrk1A in the embryonic mouse neocortex inhibits cell pro-
liferation by inducing the nuclear export and degradation of cyclin
D1.
27
A more recent study indicates that DyrkA kinase activity is
responsible for the stabilization of cellular cyclin D1 and the degra-
dation of p27 (a cyclin-dependent kinase [CDK] inhibitor) in
mouse and human cells.
28
Other authors have shown that upregula-
tion of Dyrk1A induces proliferation arrest of embryonic NPs. Con-
versely, its loss of function causes overproliferation and cell death in
the embryonic chick spinal cord and mouse telencephalon.
29
These
authors suggest that Dyrk1A is both necessary and sufficient for
transcriptional upregulation of the expression of p27. Furthermore,
Dyrk1A phosphorylates p53 in rat embryonic hippocampal
progenitors H19–7 cells, which leads to a
robust induction of p21.
30
These results
support a model in which Dyrk1A impairs
cell cycle progression of embryonic progen-
itors, especially at the transition from G1/
G0 to S phase (summarized in Fig. 1). In
contrast with these data, mnb overexpres-
sion promotes organ growth through inhi-
bition of the Salvador-Warts-Hippo
(SWH) pathway, also called the Hippo
pathway,
22
a known inhibitor of prolifera-
tion and inducer of apoptosis in flies and
mammals.
31-34
Whether these differences
are species- or tissue-specific is not known,
but throughout the text we will see more
examples of different, and even opposite,
readouts of Dyrk1A functions in different
contexts. Although there is no clear expla-
nation for this behavior this gene is
extremely dosage dependent so one could
hypothesize that changes in the level or the
duration of Dyrk1A expression could have
different consequences. There are even
cases in which both downregulation and
overexpression of DYRK1A have the same
readout.
35
Moreover, a recent study using
single-cell image analysis has shown that Dyrk1A mediates a dose-
dependent increase in the duration of the G1 phase via direct phos-
phorylation and subsequent degradation of cyclinD1, directing
PC12 cells into a reversible arrested state. In contrast, knockdown
or kinase inhibition of Dyrk1A greatly increased cyclinD1 protein
levels and split cells into 2 fates, with one subpopulation (with low
p21 expression) shortening the G1 phase and the other (with high
p21 expression) entering a persistent arrested state that differs from
the normal quiescence state in which expression of both proteins is
low.
36
Thus, both upregulation and downregulation of Dyrk1A
levels could lead to cell cycle exit (transient or irreversible, respec-
tively) and have similar consequences on tissue growth.
In addition to directly controlling the cell cycle machinery, it
has been suggested that overexpression of Dyrk1A is necessary to
induce neural differentiation, although it is not clear whether it is
sufficient for this final outcome.
27,29
Regarding the mechanism,
Yang and coworkers have shown that Dyrk1A activity is induced
during in vitro differentiation of hippocampal progenitor cells,
leading to the stimulation of cAMP responsive element binding
protein (CREB) transcriptional activity.
37
Another group has
suggested that Dyrk1A overexpression potentiates nerve growth
factor (NGF)-mediated PC12 neuronal differentiation by upre-
gulating the Ras/MAP kinase signaling pathway.
38
More
recently, it has been proposed that Dyrk1A phosphorylates
Notch in the nuclear compartment and is co-expressed with the
Notch ligand Delta1 in single NPs. Furthermore, Dyrk1A sup-
presses Notch signaling and reduces its capacity to sustain tran-
scription in neural cells, counteracting its antidifferentiative
actions.
29,39
Another interesting possibility would be that
Dyrk1A influences neuronal differentiation through the
Figure 1. DYRK1A activity blocks cell cycle progression. DYRK1A is considered primarily an inhibitor
of proliferation due to its capacity to either block (red lines) cell cycle promoters (green boxes), or
activate (green arrows) cell cycle inhibitors (red boxes).
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modulation of RE1-silencing transcription factor (REST, also
known as neuron-restrictive silencer factor or NRSF). REST is a
zinc finger transcription factor that silences a range of neuronal
genes in differentiated non-neuronal tissues and NPs.
40
Further-
more, the dissociation of REST and its co-repressors from the
RE1 sites is both necessary and sufficient to trigger the transition
from pluripotent embryonic stem cells to NPs, and from these to
mature neurons.
41
Moreover, REST is degraded in the G2 phase
and this is necessary for the derepression of Mad2, an essential
component of the spindle assembly checkpoint.
42
Reduced
expression of REST has been observed in cultured fetal DS brain
cell-derived neurospheres
43
as well as in the brains of DS mouse
models.
44,45
By inhibiting REST expression, DYRK1A might
inhibit the G2-M checkpoint (Fig. 1) as well as promote some of
the neural differentiation defects observed in DS.
In contrast to the antiproliferative and prodifferentiative capac-
ity of Dyrk1A during CNS development, we recently suggested
that this kinase sustains adult NP self-renewal.
46
In our experience,
Dyrk1A protein is actively distributed during adult NP cell divi-
sion and the inherited kinase acts as an inhibitor of epidermal
growth factor receptor (EGFR) degradation by phosphorylating
Sprouty2 (Spry2), modulator of receptor tyrosine kinases (RTK)
turnover. Interestingly DYRK1A phosphorylates T75 on Spry2
and impairs its inhibitory activity on extracellular signal-regulated
kinase (ERK) signaling downstream of fibroblast growth factor
(FGF).
47
However, Spry2 also phosphorylates and sequesters Cbl,
a major effector of EGFR degradation.
48
The data on adult pro-
genitors suggest that Dyrk1A phosphorylation could be beneficial
for the positive function of Spry2 downstream of EGFR but coun-
teractive for the inhibitory function of this protein on FGF signal-
ing (Fig. 3). Therefore, high expression of Dyrk1A should
correlate with general activation of RTK function. It would be
interesting to test whether phosphorylation by Dyrk1A modulates
the binding of Spry2 to regulatory proteins, as it has been
described for phosphorylation of other Spry2 residues.
49
In fact,
Dyrk1A overexpression decreases the interaction of Spry2 and
growth factor receptor-bound protein 2 (Grb2), an adaptor
between RTK and the ERK pathway.
50
These results suggest that
DYRK1A kinase activity could have a positive function in both
EGFR and FGFR signaling, at least in the context of the adult
CNS. In agreement with this, activation of the AKT pathway, a
known transducer of RTK activation, has been observed n several
transgenic Dyrk1A mouse models, concomitant with an increase
in expression of CCND1 (the gene coding for cyclin D1) in post-
natal and adult stages.
50,51
Together, these data suggest that
Dyrk1A might act mainly as a negative regulator of cell cycle dur-
ing neural development, but also as a positive regulator of cell pro-
liferation in the adult CNS, probably due to differential expression
of downstream substrates or regulatory molecules.
Regulation of Quiescence through the DREAM
Complex
An important group of proteins that negatively regulate the cell
cycle are the retinoblastoma (RB) tumor suppressor protein and the
related family members p107 (RBL1) and p130 (RBL2).
52
p130
has been shown to accumulate in G0, when it interacts with E2F4
to repress E2F-dependent gene transcription.
53-55
P130 and E2F4
are part of a larger multisubunit protein complex, the mammalian
DREAM (dimerization partner, RB-like, E2F, and multivulval
class B) complex.
56,57
In a recent study, phosphorylation of the
DREAM component LIN52 at S28 by DYRK1A was shown to reg-
ulate complex formation in G0 and E2F repression.
58
Inhibition of
DYRK1A activity or a point mutation in LIN52 disrupted
DREAM assembly and reduced the ability of tumor cells to enter
quiescence and the capacity of fibroblasts to undergo Ras-induced
senescence
58
(Fig. 1). These authors have shown that overexpres-
sion of DYRK1A (but not a kinase-deficient mutant) can inhibit
proliferation and colony formation of a panel of tumor cell lines
from different tissues.
58
Moreover, by phosphorylating DYRK1A,
LATS2, a component of the Hippo pathway, could enhance the
kinase activity of DYRK1A toward the DREAM subunit LIN52.
Intriguingly, the LATS2 locus is physically linked with RB1 on
13q, and this region frequently displays loss of heterozygosity in
human cancers.
59
Together, these results provide a possible expla-
nation for the proposed tumor suppressor role of DYRK1A, espe-
cially at the tumor initiation stages. However, the same mechanism
could have a protective role later on in the response to chemother-
apy. In fact, a recent report indicates that inhibition of DYRK1A
could enhance imatinib-induced cell death in gastrointestinal
tumors by favoring apoptosis at the expense of cell quiescence.
60
Documented Roles of DYRK1A in Cancer
Epidemiologic studies suggest that individuals with DS have
an increased risk of acute megakaryoblastic leukemia (AMLK)
and acute lymphoblastic leukemia (ALL) in combination with
acquired mutations of the transcription factor globin transcrip-
tion factor 1 (GATA1).
61-64
These GATA1 mutations are local-
ized in exon 2 and provoke the expression of a shorter isoform
named GATA1s.
61
However, non-DS individuals with germline
GATA1 mutations similar to those seen in DS-AMLK have no
predisposition to leukemia.
63
Moreover, trisomy for the DSCR
that includes DYRK1A markedly increases the proliferation of
megakaryocytes and is sufficient to cooperate with GATA1 muta-
tions in this mouse model, reinforcing the oncogenic function of
DYRK1A in this cell type.
65
GATA1 is essential for erythroid
and megakaryocytic development. GATA1s retains some of the
functions of the wild-type protein although it does not repress
oncogenic MYC and the proproliferative E2F.
66,67
This could
explain its oncogenic action but might also lead to a positive
feedback loop as E2F stimulates DYRK1A transcription, further
increasing DYRK1A expression.
68
In contrast to the increased risk of leukemia, individuals with
DS show a considerably reduced incidence of most solid
tumors.
69,70
It has been suggested that overexpression of
DYRK1A, in cooperation with DSCR1 (another gene located in
the DS critical region) could diminish angiogenesis through
attenuation of vascular endothelial growth factor (VEGF)-calci-
neurin- nuclear factor of activated T cells (NFAT) signaling in
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endothelial cells.
71,72
NFAT proteins are transcription factors
that are activated as a result of a calcium flux released from endo-
plasmic reticulum stores and from the activation of channels in
the plasma membrane. This increase in calcium provokes
dephosphorylation of NFAT by the phosphatase calcineurin and
its translocation to the nucleus, where it cooperates with other
factors and coactivators to promote gene transcription.
73
Since
the discovery of NFAT proteins 2 decades ago as promoters of
interleukin (IL)-2 during the activation of T cells,
74
it has
become increasingly clear that these proteins are not only
expressed in immune cells but are also overexpressed in human
solid tumors and hematologic malignancies. In general, activa-
tion of the NFAT pathway is considered to be a cancer-promot-
ing event by enhancing proliferation and survival (in T cell
lymphoid malignancies), by enhancing metastatic dissemination
(in epithelial cancers), and by promoting angiogenesis.
73,75
Phos-
phorylation of NFAT by DYRK1A
71,76
primes it for subsequent
phosphorylation by casein kinase 1 (CK1) and glycogen synthase
kinase 3 (GSK3), which drives the inactivation and nuclear
export of NFAT.
77-79
As VEGF is one of the known NFAT tar-
gets, DYRK1A overexpression could lead to decreased angiogene-
sis, thus contributing to the lower incidence of adult solid
tumors in DS individuals.
72
However, it is important to keep in
mind that DS is a multifactorial syndrome and the overexpres-
sion of other genes could be responsible for the reduced cancer
predisposition. Paradoxically, it has been proposed that
DYRK1A also contributes to megakaryocytic malignancies
through the inhibition of NFAT, although the possibility that
other substrates of the kinase are implicated in the oncogenic
response has not been excluded.
65
Therefore, it seems that while
DYRK1A and NFAT suppress the growth of epithelial and lym-
phoid tumors in the adult, they could act as megakaryocytic
oncogenes in children. This led us to hypothesize that DYRK1A
has opposite functions during normal development and carcino-
genesis of the NS and blood cells.
These context-dependent functions of NFAT have similarities
with other well-known substrates of DYRK1A and reinforce the
notion that this kinase can have different, and even antagonistic
functions, depending on the cellular context or even the cancer
stage. This idea has already been suggested by others, at least in
the DS context.
80
Figure 2 summarizes some of the DYRK1A
substrates, focusing on their pro- or antitumoral roles. For exam-
ple, NOTCH function is inhibited by DYRK1A phosphoryla-
tion, as previously mentioned.
29,39
Hyperactivation of the
NOTCH pathway has classically been viewed as oncogenic in
several cancers (solid tumors and blood cancers) although recent
studies have revealed tumor suppressor roles for NOTCH signal-
ing in myeloid malignancies.
81
Therefore, DYRK1A inhibition
in NOTCH-related cancers could have positive or negative con-
sequences for tumor growth and survival. A similar scenario
might exist for the protein REST, which has antitumor properties
in epithelial cancers but can function as an oncogene for neural
tumors.
40
REST was first identified as a cancer-related gene a
decade ago from studies in medulloblastoma (MD), a childhood
tumor of the cerebellum,
82,83
and was later also characterized as
an oncogene in neuroblastoma (NB), the most common
extracranial solid tumor in children
84
and glioblastoma (GBM),
a deadly adult brain tumor.
85,86
These data suggest that REST
controls the maintenance of embryonic and adult NPs and, when
deregulated, can be implicated in neural tumors. As we previ-
ously mentioned, REST appears to be downregulated in DS
brains. However, more recent observations indicate that REST
can activate DYRK1A transcription through a NRSE site in the
human DYRK1A promoter region. Moreover, REST and Dyrk1A
are coordinately expressed during neural development, and
DYRK1A imbalance can destabilize REST protein expression
and reduce its transcriptional activity.
35
Therefore, it seems that
in this case the regulation is even more complicated: DYRK1A
can work as a positive or a negative modulator of REST expres-
sion/activity, which in turn could have oncogenic or tumor sup-
pressor activity depending on the tissue.
Survival- or Apoptosis-Related Substrates
of DYRK1A
In contrast to the dual (pro- or antitumoral) function of some
of the genes mentioned above, there is a list of prosurvival or
antiapoptotic proteins that are activated upon DYRK1A phos-
phorylation and could be important for carcinogenesis in differ-
ent tissues (Fig. 3). Signal transducer and activator of
transcription (STAT) is a latent transcription factor that trans-
mits signals generated primarily by cell surface receptors into the
nucleus. STAT3 is transiently activated in normal cells but is
constitutively activated in a wide variety of hematologic malig-
nancies (leukemia, lymphomas, and multiple myelomas) and
solid tumors (such as head and neck, breast, lung, gastric, hepato-
cellular, colorectal, brain, and prostate cancers).
87
There is strong
evidence suggesting that aberrant STAT3 signaling promotes ini-
tiation and progression of cancer by either inhibiting apoptosis
or inducing proliferation, angiogenesis, invasion, and metasta-
sis.
88
Phosphorylation of STAT3 at position Y705 by Janus
kinase (JAK) induces its dimerization and nuclear transloca-
tion.
89
However, the STAT3 molecule contains a second phos-
phorylation site, S727, within its C terminus that can be
phosphorylated by DYRK1A
90
and is necessary to achieve maxi-
mal transcriptional activity.
89
In fact, recent data suggest that
phosphorylation at S727 plays a principal role in regulation of
cell survival activity and nuclear translocation of STAT3.
91
Nev-
ertheless, inhibition of DYRK1A has not been explored as a way
to modulate the growth of STAT3-related tumors. GLI1, a major
effector of Sonic hedgehog (SHH) signaling, is another onco-
genic transcription factor whose nuclear translocation and func-
tion seems to be mediated by DYRK1A phosphorylation, most
likely through the retention of GLI1 in the nucleus.
92
SHH-GLI
signaling regulates tumor growth and survival, as well as metasta-
sis, in a number of tumors.
93
However, although STAT3 is a
bona fide DYRK1A substrate, the relevance of GLI1 phosphoryla-
tion by the kinase and the possible applications of DYRK1A
inhibitors in SHH-dependent tumors is still under debate.
DYRK1A function has been linked to negative regulation of
the intrinsic apoptotic pathway through the phosphorylation of
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caspase-9.
94,95
Caspase-9 is activated by a variety of apoptotic
stimuli that trigger the release of cytochrome c from mitochon-
dria. Once in the cytosol, cytochrome c induces the oligomeriza-
tion of apoptotic protease activating factor 1 (Apaf-1) and the
subsequent recruitment of procaspase-9. These events lead to
activation of procaspase-9 by autocatalytic processing and conse-
quently to the activation of effector caspase-3 and caspase-7.
96
Activation of caspase-9 is inhibited by phosphorylation at T125,
which is catalyzed, among others, by Dyrk1A.
94,95
This is impor-
tant during the development of retina progenitors,
95
and in the
response of cells to hyperosmotic stress.
97
Therefore, the inhibi-
tion of DYRK1A would lead to caspase-9 induction and could
be exploited to enhance the apoptotic response of cancer cells to
chemotherapy. In addition, DYRK1A might promote cell sur-
vival through phosphorylation and activation of sirtuin 1
(SIRT1; also known as silent mating type information regulation
2 homolog or NAD (C)-dependent protein deacetylase), which
participates in the stress response and cellular metabolism.
98
It
has been shown that DYRK1A and DYRK3 directly phosphory-
late SIRT1 at T522, promoting deacetylation of p53, and, more
importantly, that the knockdown of endogenous DYRK1A and
DYRK3 sensitizes cells to DNA damage-induced cell death.
99
These data, together with the impairment of quiescence mediated
by inhibition of the DREAM complex and inhibition of the
HIPPO pathway (which induces apoptosis) by DYRK1A, suggest
that DYRK1A could be a good therapeutic target to increase cell
death in response to both chemo- and radiotherapy in different
tumors, as has been suggested by others.
100
Despite these prosurvival functions of DYRK1A, and exclud-
ing its well-known link to DS-related leukemia, it was not until
recently that our group described a clear association of this kinase
with tumor growth. Our results suggest that DYRK1A is highly
expressed in a subset of GBMs, where it correlates with the
expression and genetic amplification of EGFR. In parallel to
events in normal NPs, downregulation of DYRK1A leads to an
increase in EGFR degradation and therefore to inhibition of the
self-renewal capacity of GBM cells.
101
Furthermore, overexpres-
sion of SPRY2 was able to compensate for the EGFR degradation
promoted by DYRK1A inhibition and rescue the self-renewal
effect. On top of this, we have shown that genetic or pharmaco-
logic blockade of DYRK1A severely impaired tumor growth in
vivo, thus opening the door to the use of DYRK1A inhibitors in
glioma therapy, at least for EGFR-dependent tumors.
101
EGFR
is a well-known oncogene in a variety of tumors and inhibitors of
Figure 2. Double-edged regulation of tumorigenesis by DYRK1A. DYRK1A has been associated with protumoral activity (green boxes) by activating
(green arrows) known oncogenic proteins (red boxes) or by inhibiting (red lines) tumor suppressors (red boxes). However, an antitumoral capacity of
DYRK1A has been also described through its activation of tumor suppressors or its inhibition of oncogenic proteins. To add complexity to DYRK1A func-
tion, some of the known substrates of this kinase can have both oncogenic and tumor suppressor activities (green and red boxes), depending on the cel-
lular context and the developmental stage.
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its tyrosine kinase activity are being tested in many of these,
including GBM, although the results have not always been always
optimal.
102
Impaired endocytic downregulation of this receptor
is frequently associated with cancer. Indeed, dominant-negative
forms of CBL have been identified as oncogenes in human mye-
loid neoplasms
103
and SPRY2 has tumor-promoting activity in
colon cancer.
104
Therefore, the induction of EGFR degradation
mediated by inhibition of DYRK1A could represent an alterna-
tive strategy for EGFR-related cancers such as colon, lung, and
head and neck tumors.
To summarize this section, there is not a simple answer to the
question of whether DYRK1A functions as an oncogene or a
tumor suppressor (Fig. 2). In addition, it is important to note
that the relevance of some of the targets described above has not
been confirmed in a tumor context, or even in cancer cell lines.
Moreover, in the most conceivable situations several targets
would act in a combinatorial way. Therefore, the final response
of a cell to DYRK1A overexpression or inhibition probably
depends on the molecular and cellular context of each cancer.
DYRK1A Inhibitors and their Possible Use in Cancer
Therapeutics
In recent years there has been increased interest in inhibition
of DYRK1A activity for the treatment of the mental impairment
associated with several neurodegenerative diseases (including
Alzheimer’s Disease) and DS.
12,105
The fact that this kinase is
extremely dosage dependent increases its therapeutic potential as
a target. The goal then would be not to inhibit DYRK1A
completely but rather to a level comparable with that of healthy
conditions, which could reduce the potential side effects of tar-
geting this kinase. Most DYRK1A inhibitors are ATP competi-
tors and act by binding within the DYRK1A kinase domain
(direct competitors) or by preventing the functionality of the
ATP binding site (indirect competitors).
6
They can be classified
based on their structure (see
100
for a comprehensive review) or
based on their origin: i.e., natural compounds and their deriva-
tives, synthetic inhibitors, and broad spectrum kinase inhibitors
that show activity against DYRK1A. Table 1 reviews the most
potent DYRK1A inhibitors and their possible implications in
cancer. Many of them can inhibit other members of the DYRK
family, as well as structurally related kinases such as CDKs
(important regulators of cell cycle progression) and CDK-like
kinases (CLKs), which participate in pre-mRNA splicing.
106
Dif-
ferent modifications of these compounds have been envisioned in
order to increase specificity and avoid side effects.
Among DYRK1A inhibitors, the b-carboline alkaloid known
as harmine is currently the most selective and effective, although
it also blocks other DYRKs, especially DYRK1B. It functions as
an ATP-competitive inhibitor to specifically block the S/T kinase
activity.
6,107
Harmine is isolated from divergent plant species,
including the South American vine Banisteriopsis caapi and the
mideastern shrub Peganum harmala. It is a component of ayahua-
sca, a hallucinogenic brew of plant extracts that has been used for
centuries in healing and to cure illnesses, including some types of
cancer. However, several active principles could be involved in
this action and there is no direct evidence that targeting
DYRK1A is the relevant anticancer action of ayahuasca.
108
Har-
mine has been shown to inhibit neovessel formation in vitro and
in vivo through the regulation of several angiogenic factors and
inflammatory cytokines.
109
Moreover, harmine and related
b-carboniles display cytostatic and/or cytotoxic activity toward
cancer cells, including leukemia, colon, liver, gastric, and glioma
cells.
65,101
,
110-114
However, harmine has long been known to be
a potent inhibitor of monoamine oxidase-A
115
and to have hallu-
cinogenic properties as a result of its affinity for the tryptamine
and serotonin receptor binding sites.
116
These properties seri-
ously limit the in vivo therapeutic applications of this compound.
Nonetheless, molecular docking analysis showed that harmine
has many degrees of freedom in the ATP-binding pocket of
DYRK1A and this could be exploited to more selectively inhibit
the kinase.
117
Glioma cells are also sensitive in vitro to INDY, a
benzothiazol derivative.
101
The in vitro biological activity of
INDY has been confirmed to involve blockage of Tau phosphor-
ylation and restoration of NFAT activity, and it can rescue the
developmental defects of Dyrk1A overexpressing tadpoles in
vivo.
105,118
However, nothing is currently known about the phar-
macokinetic properties of this compound in whole animals or
humans, which hampers its therapeutic use. Another 2 synthetic
compounds, lamerallins and meriolins, have shown some anti-
cancer and proapoptotic effects in cancer cells and mouse glioma
models, although other kinases (especially CDKs) could be
implicated in this activity.
119-123
Epigallocatechin gallate (EGCG) is a polyphenol and a major
catechin component of green tea that shows selective inhibition
of DYRK1A compared to other structurally and functionally
related kinases by functioning as a noncompetitive inhibitor of
ATP.
124
Interestingly, a diet rich in green tea clearly improved
the brain structure defects and cognitive impairments of
DYRK1A-overexpressing mice.
51
EGCG has been shown to have
anticancer activity by inhibiting topoisomerases I/II, the antia-
poptotic enzyme Bcl-xl, and cancer promoting proteases. More-
over, it has additional health properties as it shows potent
antibacterial and antiviral activity and elicits antioxidative and
anti-inflammatory capacity by suppressing the nitric oxide syn-
thase pathway.
105
Although it seems clear that the anticancer
activities of green tea and EGCG are not limited to DYRK1A
inhibition, their safety for human consumption make them good
candidates for use in DYRK1A-related tumors and neurodegen-
erative diseases.
Most of the inhibitors mentioned in Table 1 have the capacity
to block other DYRK proteins, especially the closely related
DYRK1B (also known as MIRK). MIRK has been characterized
as a negative regulator of cell proliferation that modulates the
protein stability of several cell cycle-related molecules.
125,126
However, upregulation of MIRK expression and/or constitutive
activation of this kinase has been observed in several different
types of cancer, where it has been associated with the survival of
tumor cells in response to stress.
127
For example, depletion of
Mirk has been associated with apoptosis in lung cancer
128
and
also in pancreatic and ovarian cancer cell lines, where it seems to
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modulate the levels of reactive oxygen species (ROS).
129-131
Therefore, the effect of some DYRK1A inhibitors in cancer could
also be due to MIRK inhibition, especially if they are associated
with changes in the response of tumor cells to hypoxia, nutrient
deprivation, and/or cytotoxic stimuli.
Conclusions and Future Perspectives
The results of several in vitro and in vivo studies link
DYRK1A activity with cell cycle exit, oncogene-induced senes-
cence, and cell differentiation, especially in the embryonic NS.
This notion is reinforced by the nature of many known DYRK1A
substrates, and also by the decreased cancer susceptibility of indi-
viduals with DS. Therefore one would expect this gene to behave
as a tumor suppressor, at least for the initial cancer stages. How-
ever, recent evidence indicates that DYRK1A can induce clono-
genic and prosurvival properties in certain types of cell or in
certain developmental conditions, and that this kinase can be
considered as an oncogene for at least 2 types of cancer: myeloid
leukemias and gliomas. As a proof of principle, harmine, a potent
DYRK1A inhibitor, can block cell growth and tumorigenesis in
those tumors. Moreover, DYRK1A might confer chemo- and
radioresistance capacities in several tumors by controlling the bal-
ance between quiescence and apoptosis. We propose that newly
identified DYRK1A inhibitors, which are being developed pri-
marily for their use in mental diseases, should also be considered
as anticancer agents, at least for AMKL and GBM. Moreover,
considering the relevance of DYRK1A in the NS, it would be
important to test the efficacy of such inhibitors in other neural
tumors such as oligodendrogliomas, which express high levels of
DYRK1A, and MB, given the important cerebellar expression of
this kinase. In such brain tumors, the regulation of EGFR turn-
over by DYRK1A might participate in the oncogenic action of
this kinase, in addition to modulation of REST, which is highly
expressed in cerebellar NPs, and SHH and/or NOTCH signal-
ing, which are associated with NS development. Special attention
should be given to secondary hits of DYRK1A inhibitors and to
the fact that DYRK1A blockade could affect several pathways.
However, in the case of cancer some promiscuity may be
Table 1. DYRK1A inhibitors. The table shows the IC
50
of different classes of DYRK1A inhibitors against DYRK1A, other DYRK proteins, and different kinases
(only targets with submicromolar IC
50
values are included). Cancer-related studies performed with those inhibitors are also indicated
Compound name
IC
50
(nM)
Evidence related to cancer
(Chemical class) DYRK1A Other targets therapy Refs.
Natural inhibitors Harmine (b-carboline) 22–400 DYRK1B (166–300), DYRK2 (900–
1,900), DYRK3 (800–1000), DYRK4
(80,000), MAO-A (5), CLK1 (27)
Angiogenesis inhibition;
Cytotoxic activity in tumor cell lines
in vitro (glioma, leukemia, colon,
gastric, liver), and in vivo (glioma)
101,107,111–115,117
EGCG (Polyphenol) 40–330 Vimentin (3), COMT (70) Clinical trials on cancer: urothelial,
bladder, prostate, myeloma, breast,
lung
124,132,133
Staurosporine (glycosilated
indolocarbazole)
20 Aurora A (7.2), Aurora B (20), Chk1
(1), Ftl3 (3), HGK (1), Ikkb (0.5), Jak2
(1), KDR (10), SYK (4)
134
Synthetic inhibitors Lamerallins (Chromenoindole) 40–5,000 CDK5 (720->10,000), GSK3 (310-
>10,000), CDK1/CyclinB, PIM1, CK1
(70–8,000)
Apoptosis induction and multidrug
resistance phenotype reversion
119–121,135
INDY (Benzothiazol) 200 DYRK1B (240) Antiproliferative in gliomas
101,118
Meriolins (Pyrimidinylindol/
azaindol)
30 CDK1 (7–170), CDK2 (3–18), CDK5
(3–170), CDK9 (5.6–18), GSK3 (21–
400), CK1 (50–200)
Antiproliferative and proapoptotic
effects in tumor cells and glioma
xenografts
122,123
Variolin B (Pyrimidinylindol/
azaindol)
80 CDK1 (60), CDK2 (80) CDK5 (90)
CDK9 (26) GSK3 (70) CK1 (5)
122
Meridianins (Pyrimidinylindol/
azaindol)
34–900 CDK5 (680->10,000), CK1 (490-
>10,000), CLK1 (30–70)
136,137
KHCB19 (dichloroindol) 55 CLK1 (20), CLK3 (500)
138
Imidazolone (Leucettamine) 70–1,000 CLK1 (15–71), GSK3(21–38)
139
Promiscuous
kinase inhibitors
Purlavanol A (Purine) 300 CDK2 (30–100), PAK4 (100), SRC
(<100 ), CDK2/CyclinA (100)
107,124
A-443654 (Pyridine) <10 DYRK2, DYRK3 (<100 ), ERK8, RSK1,
RSK2, PKBa, PKBb, S6K1, PKA,
ROCK2, PRK2, PKCa,PKD1,MSK1,
SmMLCK, SK3b, CDK2-CyclinA,
PIM1,2,3,MST2,HIPK2 (<100 )
Initially identified as a potent Akt
inhibitor for use in anticancer
research field
140
TBB, TBI, DMAT, TDI (Tetrahalo-
bicycles)
100–10,000 DYRK2 (300–35,000), DYRK3 (2,000–
5,000), CK2 (100–600), PIM1 (100–
1,000), PIM2 (200–4,000), PIM3 (70–
1,000)
117,141–143
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acceptable and might even represent an advantage, further
encouraging the preclinical and clinical analysis of such com-
pounds in cancer therapeutics.
Disclosure of Potential Conflicts of Interest
No potential conflicts of interest were disclosed.
Funding
This study was supported by grants from Ministerio de Econ-
omıa y Competitividad, Fondo de Investigacion Sanitaria, PI12/
00775 and from Ministerio de Economıa y Competitividad, Red
Tematica de Investigacion Cooperativa en Cancer (RD12/0036/
0027) to PSG.
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