Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Dyrk1a

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101613

Synonyms

Historical Background

DYRK1A is a member of the Mnb/DYRK subfamily of protein kinases, which falls within the CMGC Ser/Thr family to which cyclin-dependent kinases (CDKs), CDC-like kinases (CLKs), glycogen synthase kinase (GSK3), and mitogen-activated protein kinase (MAPK) also belong. The founding member of the Mnb/DYRK subfamily in multicellular organisms was identified in Drosophila melanogaster (Dm) and due to the reduced brain size associated with its loss of function it was named minibrain (mnb). This phenotype is caused by altered proliferation during brain development, suggesting a key function for this kinase in the regulation of neural proliferation and neurogenesis (Tejedor et al. 1995). In addition, mnb mutant flies have behavioral defects, indicative of alterations to neuronal activity. The rat Mnb ortholog was independently cloned, identifying unusual structural features and biochemical properties of this novel protein kinase (Kentrup et al. 1996). This protein was called Dyrk1 (Dual specificity tyrosine (Y)-phosphorylation Regulated Kinase) due to its ability to perform Tyr autophosphorylation and Ser/Thr phosphorylation in exogenous substrates. Interestingly, the human MNB/DYRK1A ortholog maps to the Down syndrome (DS) critical region (Guimera et al. 1996), and it is overexpressed in the fetal and adult DS brain. These seminal publications have greatly influenced research into this protein kinase and thus, most initial efforts were oriented toward understanding its role in neurodevelopment, its implications in DS neurobiology and its unique biochemical properties (reviewed by Becker and Sippl 2011; Tejedor and Hammerle 2011). The highly conserved protein structure of the Mnb/Dyrk1A kinase orthologs (reviewed in Aranda et al. 2011) prompted extensive studies in mouse mutants and DS mouse models. Remarkably, transgenic mice overexpressing Dyrk1A experience neurodevelopmental delay and cognitive deficits (Altafaj et al. 2001), and haploinsufficient Dyrk1A +⁄- mice have smaller brains (Fotaki et al. 2002), strongly suggesting evolutionary conserved functions in brain development.

Although Mnb/Dyrk1A homologs have been identified from yeast to humans (reviewed in Aranda et al. 2011), the deletion of mbk-1 (the closest homologue in Caenorhabditis elegans) does not cause morphological alterations in any tissue, and if we also consider that there are also some differences in protein structure (see below), it would appear that most relevant cellular functions of Mnb/Dyrk1A emerged during evolution from insects on. Accordingly, only data from Dm Mnb to human DYRK1A will be discussed here and the structurally distinguishable (see below) vertebrate paralog involved in muscle development and tumorigenesis, Dyrk1B/Mirk, will not be considered either.

Protein Structure and Biochemical Properties of DYRK1A

The Mnb/DYRK kinase subfamily, which includes mammalian DYRK1A, DYRK1B, DYRK2, DYRK3, and DYRK4 (see Aranda et al. 2011 for a detailed phylogenetic analysis), is characterized by specific sequence motifs in the catalytic domain. Nevertheless, Mnb/DYRK1A orthologs display several unique structural features outside the kinase domain (Fig. 1, see also http://www.uniprot.org/uniprot/P49657 and http://www.uniprot.org/uniprot/Q13627 for details of the Dm Mnb and Human DYRK1A proteins, respectively). Thus, in addition to the DYRK homology (DH) box, specific to all DYRK kinases, the N-terminal of Mnb/DRK1A contains a bipartite nuclear localization signal (NLS) that targets DYRK1A to the nucleus. There is another NLS harbored within the kinase domain of DYRK1A (and possibly in Dm Mnb too) but not in that of the DYRK1B paralogs. The amino-terminal also contains a motif for binding to adaptor WD40 repeat domain proteins like DCAF7/HAN11, WDR68. It has also been proposed recently that a basic patch comprising part of the N-term NLS domain may bind directly to tubulin. A PEST motif (rich in proline, glutamic acid, serine, and threonine), putatively involved in rapid protein degradation, is located at the carboxy-terminal of the kinase domain. A histidine repeat (His-rp), possibly involved in localization to nuclear splicing speckles, and a serine/threonine repeat (S/T-rp) of unknown function are also located in the C-terminal of vertebrate Mnb/DYRK1A orthologs but not in DYRK1Bs. The Dm mnb gene encodes several alternative C-terminal splice isoforms (Tejedor et al. 1995: see updated information at http://flybase.org/cgi-bin/gbrowse2/dmel/?Search=1;name=FBgn0259168), all of which show significant sequence homology in the C-terminus to mammalian DYRK1As although lack the His and S/T repeat domains. They also contain a GAS domain (rich in Glycine, Alanine, and Serine) which fulfills a similar function to the vertebrate PEST domain. In addition, the Dm Mnb long isoforms contain an Alanine repeat (Ala-Rp) and a Serine rich (Ser-Rp) motif of unknown function. By contrast, although the Caenorhabditis elegans homolog, Mbk-1, is highly conserved in the catalytic domain and DH-box, it differs in its nuclear localization and C-terminal structure.
Dyrk1a, Fig. 1

Schematic representation of the protein domain structure of mammalian DYRK1A and Dm Mnb. ActL activation loop, Ala-rp Alanine repeat, DH DYRK homology box, His-rp Histidine repeat, NLS nuclear localization signal, PEST proline-, glutamic acid-, serine-, threonine-rich region, S-rp serine repeat, S/T-rp serine/threonine repeat, WD binding motif to adaptor WD40 repeat domain proteins

A very unusual property of Mnb/DYRK1A kinases is that they are switched on by autophosphorylation of a Tyr-X-Tyr motif in the activation loop located within the catalytic domain (Kentrup et al. 1996). Remarkably, this Tyr-phosphorylation is irreversible and independent of regulatory signals. Moreover, it takes place only on a transitory intermediate form of the kinase during protein translation, leading to the constitutive activation of the kinase (Lochhead et al. 2005). Subsequently, the mature active kinase only phosphorylates substrates at Ser/Thr residues (reviewed by Becker and Sippl 2011).

Pioneering work with a peptide library designed according to putative substrate sequences defined DYRK1A as a proline-directed kinase with a RPX(S/T)P phosphorylation consensus sequence and accordingly, a peptide (DYRKtide) with the optimal substrate sequence was designed (Himpel et al. 2000). Nevertheless, the identification of non-consensus phosphorylation sites in several putative substrates suggests that DYRK1A is not strictly a proline-directed kinase. Thus, DYRK1A appears to be a pleiotropic protein kinase capable of phosphorylating a plethora of substrates in vitro or when overexpressed in diverse cell systems. Nevertheless, only a fraction of these substrates have been verified in vivo, and therefore, the majority should only be considered as putative substrates (Table 1). As described below, these substrates are involved in quite diverse cell processes.
Dyrk1a, Table 1

Substrates and interactors of Dyrk1A arranged into functional subgroups

Cell function subgroup

Protein

Molecular nature

Molecular Relation with Dyrk1A

Biological function

Cell cycle regulation

Cyclin D1

Regulatory subunit of cyclin-dependent kinases (CDKs)

S (iv)

Proliferation of neural progenitors

Cyclin D3

Regulatory subunit of cyclin-dependent kinases (CDKs)

S

Proliferation of lymphocyte precursors

LIN52

Subunit of the DREAM complex

S

Quiescence/senescence of tumor cells

p27Kip1

Cyclin-dependent kinase inhibitor (CKI)

S (iv)

ExpR (iv)

Neurogenesis and neuronal differentiation

Cell death regulation

ASK1

Apoptosis signal regulation kinase

S

UF

Caspase 9

Cysteine aspartyl protease

S (iv)

Programed cell death of neurons

SIRT1/Sir2

NAD-dependent protein deacetylase

S

Food intake

Cytoskeleton Regulation

ABLIM1

Actin regulatory protein

S

UF

MAP1B

Microtubule associated protein

S (iv)

Neuronal differentiation

N-WASP

Regulator of actin cytoskeleton

S

Neuronal differentiation

SEPT4

GTPase and cytoskeleton scaffolding protein

S (iv)

Neuronal differentiation

TAU

Microtubule-associated protein

S, $ (iv)

Neuronal differentiation, neurodegeneration

β-tubulin

Microtubules component

S (iv)

Dendritogenesis

Gene Expression Regulation

Arip4

Steroid hormone receptor cofactor, chromatin remodeling

I, S

UF

Capicua (Cic)

Transcriptional repressor of receptor tyrosine kinase/ERK pathway

I, S

Tissue growth

CREB

cAMP responsive transcription factor

S

Neuronal differentiation

CRY2

Cryptochrome TF

S (iv), $

Circadian regulation

FKHR /FOXO1

Transcription factor

S, I

UF

GLI1

Transcription factor, oncogene

S

Proliferation

Histone H3

Chromatin remodeling

S

UF

INI1/SNF5, SNR1

Component of the SWI/SNF

chromatin remodeling complex

S, I

UF

NFAT

Transcription factor

S (iv), $

Tissue growth, cell proliferation

NRSF/REST

Neuron-restrictive transcriptional regulator

S, ExpR (iv)

Cell proliferation, differentiation

p53

Transcription factor

S (iv)

Neural proliferation

RNAPII

RNA polymerase

S

UF

STAT3

Transcription factor

S (iv)

Astrogliogenesis

Membrane

trafficking

Amphiphysin

Protein of synaptic vesicles

S

Synaptic function

DNM1

GTPase

S (iv)

Dendritogenesis, synaptic function

Endophilin 1

Endocytosis regulatory protein

I (iv)

Synaptic function

Munc18–1

Regulator of exocytosis

S (iv)

Synaptic function

Synaptojanin 1 (Synj)

Endocytosis regulatory protein

S (iv)

Synaptic function

α-synuclein (SNCA)

Possible regulator of synaptic vesicle release

S

UF

mRNA processing

ASF

Splicing factor

S, I (iv)

UF

Cyclin L2

Splicing factor

S

UF

SF3b1/

SAP155

Splicing factor

S

UF

SRp55

Splicing factor

S

UF

9G8

Splicing factor

S

UF

Transmembrane receptor signaling

APP

Amyloid precursor protein

S

UF

GluN2A

Subunit of NMDA receptors

S

Synaptic function

Notch

Cell-cell signaling transmembrane receptor protein

S, (iv)

Neuronal differentiation

P120-catenin

Component of non-canonical WNT signaling

S

UF

Presenilin1 (PS1)

Component of the γ-secretase complex

S

UF

Sprouty 2 (SPRY2)

Modulator of growth factor receptor signaling

S (iv)

Adult neurogenesis

Warts (Wts)

Protein kinase of the Hippo pathway

S

Tissue growth

Miscellaneous

eIF2B

protein-synthesis initiation factor

S,$

Protein translation

Glycogen

synthase

Glycogen

synthase

S

Metabolism regulation

Parkin

E3 ubiquitin ligase

S

UF

RCAN1/DSCR1

Regulator of calcineurin

S, $ (iv)

UF

SIRT1/Sir2

NAD-dependent protein deacetylase

S, (iv)

Food intake

Since Mnb/Dyrk1A is a very pleiotropic protein kinase, only substrates/interactors for which at least cellular or functional evidence were reported are included in this table. Among them, those confirmed in proper in vivo studies are highlighted (iv). Abbreviations: ExpR expression regulation, I interactor, S substrate, $ priming of GSK3 phosphorylation, UF unknown function

Cellular Functions of DYRK1A

Based on the molecular nature of its putative substrates and interactors, as well as the cellular phenotypes caused by its mutations, Mnb/DYRK1A would appear to participate in the regulation of a wide repertoire of cell functions (Table 1), some of which deserve particular mention.

Given the phenotype of Dm mnb mutants, the regulation of the cell cycle of neural progenitors by Mnb/DYRK1A has been studied extensively, identifying several targets and underlying mechanisms (Table 1, Fig. 2). Thus, Dyrk1A appears to control the duration of G1 in neural progenitors by promoting Cyclin D1 turnover through its direct phosphorylation (Soppa et al. 2014). A similar action on CycD3 has been implicated in lymphoid development. On the other hand, the phosphorylation of p27Kip1, the main cyclin-dependent kinase inhibitor (CKI) in the mammalian CNS, results in its stabilization, possibly facilitating the differentiation of neuronal precursors (Soppa et al. 2014). Remarkably, Mnb/DYRK1A also promotes the expression of p27Kip1 through the regulation of a transcriptional network to trigger the cell cycle exit of neuronal precursors (Hammerle et al. 2011; Shaikh et al. 2016). Antiproliferative effects of DYRK1A in neural progenitors have been also proposed to be mediated through p53 phosphorylation and the subsequent expression of p21cip1, another CKI. Similarly, Dyrk1A appears to control the G1 entry/exit decision in fibroblasts by regulating the relative levels of CycD1 and p21cip1. Interestingly, DYRK1A was seen to facilitate cell cycle exit of tumor cells by phosphorylating the DREAM complex subunit LIN52, thereby promoting the assembly of this repressor complex, leading to the silencing of E2F cell cycle target genes and driving their entry into quiescence/senescence (Tschöp et al. 2011).
Dyrk1a, Fig. 2

Schematic summary of main molecular actions of Mnb/DYRK1A on cell cycle regulation as described in the text. DYRK1A exerts positive effects (red arrows) on negative cell cycle regulators and negative effects (black T shaped arrows) on positive regulators

Although Mnb/Dyrk1A has mainly been attributed an antiproliferative role (reviewed by Tejedor and Hammerle, 2011), there are some cases in which it seems to promote growth. This is the case in Drosophila larval imaginal discs (the eye, wing, and leg primordia), where Mnb promotes Salvador-Warts-Hippo (SWH) signaling (Degoutin et al. 2013). These apparently conflicting data might be due to distinct functions of Mnb/DYRK1A in neural and non-neural progenitors. There have also been a few, yet consistent, reports on how DYRK1A could regulate cell death/survival by phosphorylating well-known effectors like ASK1, Caspase 9, and SIRT1/Sir2 (Table 1).

Another prominent function of DYRK1A is in the regulation of the cytoskeleton. A number of regulators of both actin (ABLIM1, N-WASP) and microtubules (MAP1B, TAU, and β-tubulin) are phosphorylated by Mnb/DYRK1A, and there are compelling data showing that these actions may influence neuritogenesis, dendritogenesis, synaptogenesis, and synaptic plasticity (reviewed by Tejedor and Hammerle 2011).

There is also compelling evidence for the involvement of DYRK1A in the regulation of gene expression. Thus, DYRK1A can phosphorylate several transcription factors (CREB, FKHR/FOXO1, GLI1, NFAT, NRSF/REST, p53, STAT3), regulating their activity, stability/degradation, or nuclear-cytoplasmic trafficking. These actions can affect specific functions such as growth, proliferation, differentiation, or precursor cell specification, although detailed functional studies are scarce (Table 1; reviewed by Tejedor and Hammerle 2011). In addition, it has been reported that Mnb/DYRK1A may have a broad effect on gene transcription by acting on chromatin remodeling regulators like the SWI/SNF complex and Histone 3, or by regulating RNA polymerase II. However, the functional consequences of these actions remain to be elucidated. Furthermore, there is increasing evidence for the involvement of DYRK1A in the regulation of mRNA splicing through the phosphorylation of several splicing factors (see Table 1). Nevertheless, with the exception of the effect on the splicing of Tau mediated by ASF, again very little is known about their functional consequences.

Mnb/DYRK1A has also emerged as a key regulator of membrane trafficking (Table 1), particularly at the synapse. Remarkably, key components of the endocytic machinery like amphiphysin, dynamin 1, endophilin 1, and synaptojanin (Synj) have been identified as substrates/interactors of Mnb/DYRK1A, possibly allowing these interactions to be modulated in an activity dependent manner (Xie et al. 2012 and refs. therein). Remarkably, Dm Mnb is required for synaptic growth and synaptic vesicle endocytosis in vivo through the regulation of Synj activity (Chen et al. 2014).

Regulation of DYRK1A and its Involvement in Cell Signaling

In contrast to the information available about its downstream targets, very little is known about the upstream pathways that regulate the gene expression, activity, and subcellular localization of DYRK1A (reviewed by Becker and Sippl 2011, Table 2). As the Mnb/DKRY1A kinase is constitutively activated during translation, it is currently assumed that changes in its expression are translated into changes in its activity. Thus, Mnb/DKRY1A expression appears to be tightly regulated, although very few underlying mechanisms have been proposed to date, and even fewer have been assessed in vivo (Table 2). Thus, two homologous neuropeptides, NPY/sNPF, modulate Mnb/DYRK1A expression through the PKA-CREB axis, playing a key role in the regulation of food intake (Hong et al. 2012). Mnb/Dyrk1A expression is also regulated by miR-199b, a direct calcineurin/NFAT target involved in cardiomyocyte growth (Da Costa Martins et al. 2010). Interestingly, some regulators of its expression (CREB, NFAT, p53, and REST) are direct targets of Mnb/DYRK1A (Table 1), which points to possible feedback and feedforward mechanisms (Fig. 3).
Dyrk1a, Table 2

Regulators of activity and expression of DYRK1A

Regulator group

Protein

Molecular nature or function

Molecular action

Possible cell function

Regulators of DYRK1A kinase activity

DCAF7/HAN1/ WDR68

Wap/Riq

WD40 repeat domain proteins

Interactor (iv)

Cell proliferation,

E1A

Viral oncogene

Interactor

Oncogenic transformation

LATS2,

Protein kinase of the Hippo pathway

Phosphorylation

Cell proliferation

14–3-3

14–3-3 family of regulating proteins

Interactor

UF

Regulators of DYRK1A expression

β-amyloid (Aβ)

Peptide derived from APP. Main component of amyloid plaques in Alzheimer disease

ND

Neurodegeneration

CREB

Transcription factor

Transcription downstream of NPY/sNPF signaling (iv)

Food intake

E2F1

Transcription factor

Transcription

Cell cycle

miR-199b

MicroRNA

mRNA regulation downstream of NFAT (iv)

Cell proliferation

miR-1246

MicroRNA

mRNA regulation downstream of p53

UF

NRSF/REST

Neuronal transcriptional repressor

Transcription (iv)

Neuronal differentiation

Actions assessed in proper in vivo studies are highlighted (iv). Abbreviations: ND not determined, UF unknown function

Dyrk1a, Fig. 3

Involvement of Mnb/DYRK1A in cell signaling. DYRK1A exerts positive (red arrows) and negative (black T shaped arrows) effects on several factors as described in the main text. Signaling cascades are indicated by blue dotted arrows

There is also little information on the regulation of Mnb/DYRK1A activity. There are indications that the intracellular distribution and compartmentalization of DYRK1A may depend on its differential phosphorylation, although the kinases that putatively regulate these events are unknown. Possible regulators of Mnb/DYRK1A could be found among the interactors identified in various high-throughput analyses. Thus, a summary of the genetically generated interactome of Dm Mnb can be found in Flybase (http://flybase.org/cgi-bin/get_interactions.html?items=FBgn0259168&mode=ppi) and putative DYRK1A interacting proteins can be found in the MINT database (http://mint.bio.uniroma2.it/index.py). Unfortunately, there are currently no functional assessments available, except for that of DCAF7 that has repeatedly been shown to be a substrate recruiting subunit of DYRK1A. Interestingly, its Drosophila ortholog Wap/Riq associates with Mnb in response to signaling from the atypical cadherins Fat and Dachsous, thereby inducing phosphorylation-dependent inhibition of the Hippo pathway kinase Warts and promoting tissue growth (Fig. 3, Degoutin et al. 2013). Strikingly, LATS2, the mammalian Warts ortholog, appears to phosphorylate DYRK1A and enhances its antiproliferative action through the DREAM complex (Fig. 3, Tschöp et al. 2011). These apparently conflicting results might be due to differences in cell context, evolutionary functional divergence or to a possible regulatory feedback loop.

Although Mnb/DYRK1A has not been clearly associated with a particular signaling pathway, there are abundant data showing that it can interact with and modulate diverse cell signaling mechanisms (summarized in Fig. 3). Unfortunately, only some of these have been assessed in clear functional contexts. Thus, the inhibition of NFAT signaling by its direct phosphorylation by Mnb/DYRK1A or through phosphorylation of RCAN1/DSCR1, an inhibitor of the calcium/calmodulin-dependent phosphatase calcineurin (Caln) that regulates NFAT nuclear translocation, alters a range of developmental processes (Arron et al. 2006; Wang et al. 2015). Interestingly, DYRK1A promotes EGFR stability by preventing its endocytosis-mediated degradation through the phosphorylation of SPRY2, participating in the regulation of self-renewal and cell-fate of adult neural stem cells (Ferron et al. 2010). A similar action on SPRY2 has been described for FGF–MAPK signaling although its function is unknown. DYRK1A represses Delta/Notch signaling to facilitate neuronal differentiation through a yet unknown mechanism (Hammerle et al. 2011). Two DYRK1A-modulated arms within the mammalian Hh signaling cascade have also been described. On one hand, DYRK1A can stimulate Hh signaling by phosphorylating and retaining GLI1 in the nucleus; on the other, DYRK1A can inhibit Hh signaling by destabilizing GLI1 through a complex cascade that begins with the actin regulator ABLIM (Schneider et al. 2015 and references therein). These opposing effects of DYRK1A could be cell-type specific or depend on its level of expression. Additionally, DYRK1 can modulate Ca2+ signaling in neurons by phosphorylating NMDA receptors. Finally, the capacity of DYRK1A to act as a priming kinase for several GSK3 substrates (e.g., CRY2, eIF2B, MAP1B, NFAT, RCAN1, and TAU) strongly suggests that DYRK1A might also modulate GSK3 mediated pathways.

Pathological Implications of DYRK1A Dysfunction

The evidence of several roles for DYRK1A in neurodevelopment (neural proliferation, neurogenesis, and neuronal differentiation) and neuronal functions (particularly, synaptic functions) have sustained the hypothesis that DYRK1A overexpression has a major contribution to DS mental retardation (Tejedor and Hammerle 2011, Fig. 4). This idea has been reinforced by evidence from DS mouse models and transgenic mice overexpressing Dyrk1A, which display several neurobiological alterations reminiscent of DS. Thus, DYRK1A is presently considered a suitable drug target for DS therapy (reviewed by Becker et al. 2014). Remarkably, happloinsuficiency of DYRK1A causes an intellectual disability syndrome characterized by microcephaly (see an overview in GeneReviews®http://www.ncbi.nlm.nih.gov/books/NBK333438/). Indeed, reduced expression or activity of Mnb/DYRK1A provokes neuronal deficits in the developing Drosophila and vertebrate brain (Tejedor et al. 1995; Fotaki et al. 2002), inducing cell death after the failure of neuronal precursor to exit the cell cycle and differentiate (Hammerle et al. 2011, Shaikh et al. 2016). Together these data highlight how sensitive neurodevelopmental processes are to DYRK1A dosage imbalance (Fig. 4).
Dyrk1a, Fig. 4

Increased (red arrow) or decreased (black arrow) activity/expression of DYRK1A can alter several pathogenic pathways. See description in the main text

The fact that DS individuals develop Alzheimer’s disease (AD) precociously and that increased DYRK1A expression has been found in AD brains prompted intense research into the implications of DYRK1A in neurodegeneration. Significantly, several neurodegeneration related proteins (APP, Parkin, Presenilin 1, SEPT4, α-Synuclein, and TAU) have been identified as DYRK1A substrates. Furthermore, Tau is hyperphosphorylated in transgenic mice that overexpress Dyrk1A, and Aβ levels are elevated. As mentioned before, DYRK1A could also contribute to neurofibrillary degeneration by dysregulating TAU splicing. Thus, there is compelling evidence that DYRK1A overexpression can contribute to neurofibrillary and amyloidogenic degeneration by deregulating multiple pathways (Fig. 4, reviewed by Wegiel et al. 2011).

Again, the observation that DS individuals have an increased risk of leukemia and a decreased risk of solid tumors, in conjunction with the functions of DYRK1A in cell cycle regulation and its interaction with tumor related signaling pathways (e.g., EGFR, Hh, Hippo, and NOTCH) make DYRK1A a focal point in cancer research. Thus, it has been proposed that DYRK1A may contribute to leukemogenesis by dysregulating NFAT and to glioblastoma growth by enhancing EGFR signaling. There is also evidence that DYRK1A may modulate the activity of viral oncoproteins.

Finally, it should be noted that DYRK1A has also been implicated in the deregulation of pathogenic pathways involved in heart failure (i.e., NFAT: Da Costa Martins et al. 2010), and that DYRK1A inhibitors promote NFAT mediated β-cell proliferation (Wang et al. 2015). Accordingly, DYRK1A is now being considered a possible target for certain therapeutic approaches aimed at managing diabetes.

Summary

DYRK1A is a pleiotropic protein kinase capable of phosphorylating a large and molecularly diverse repertoire of substrates, although the true cell context and biological function of these events often remain to be elucidated or confirmed in vivo. Nevertheless, compelling data implicate DYRK1A in the regulation of quite diverse cellular functions like cell cycle, cell death, cytoskeleton dynamics, gene expression, membrane trafficking, mRNA processing, and transmembrane receptor signaling. The functional diversification reflecting its molecular pleiotropicity is further enhanced by the capacity of DYRK1A to modulate quite diverse cell signaling pathways (EGFR, Hh, Hippo, Notch, etc).

The highly conserved structure and the picture emerging from the still limited comparative studies make it likely that most biological functions of DYRK1A are to a large extent evolutionarily conserved. By contrast, it is possible that some cellular functions might work in divergent (even opposing) directions in different tissues, as is the case for the antiproliferative effects in the larval brain relative to the promotion of growth in larval imaginal discs of Drosophila. It remains to be determined whether these divergent effects could be due to different levels of expression, or to the presence/absence of certain targets or regulators of DYRK1A activity.

The functional diversity of DYRK1A is producing an increasing number of reports on its pathological implications (cognitive deficit, neurodegeneration, cancer, etc.), which is driving efforts to identify and develop new inhibitors for therapeutic strategies. Nevertheless, as several cell functions have been found to be particularly sensitive to DYRK1A dosage and some dysfunctions have been described for both excessive and defective activity/expression of DYRK1A, progress in this area will be particularly challenging. An additional difficulty in this regard will be to design inhibitors sufficiently specific for DYRK1A and that do not interfere with structurally related kinases like DYRK1B and CLKs. Finally, further efforts to increase the scarce information on the upstream mechanisms that regulate DYRK1A expression and activity will greatly help to understand better the functional framework of this increasingly important signaling molecule.

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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Instituto de NeurocienciasCSIC and Universidad Miguel Hernandez-Campus de San JuanSant Joan (Alicante)Spain