Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Microtubule Affinity Regulating Kinase-4

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101744

Synonyms

Historical Background

Microtubules (MTs) are regulated by a large number of proteins and factors. One of the classes of protein that act as a regulator of microtubules are microtubule-associated proteins (MAPs) like tau, MAP2, and MAP4 (Mandelkow and Mandelkow 1995). MAPs are widely found in the brain of vertebrates and have been studied in detail (Illenberger et al. 1996). The protein kinases like MAP/microtubule-affinity regulating kinases (MARK) phosphorylate these MAPs and regulate their activity (Drewes et al. 1997).

Microtubule-affinity regulating kinase 4 (MARK4) was first discovered in the brain of Alzheimer’s disease (AD) patients. Overexpressed MARK4 phosphorylates tau on Ser262 in the microtubule-binding domain, present within the KXGS motifs (Drewes et al. 1997). This is a critical residue which determines the binding efficiency of tau protein with the MTs. It is one of the earliest sites that gets phosphorylated after which many other protein kinases like GSK-3β hyperphosphorylates different tau epitopes clustering the microtubule-binding domain (Hernandez et al. 2013). Hyperphosphorylated tau dissociates from MTs and destabilizes the MT dynamics. The phospho-tau protein aggregates in the form of paired helical fragments (PHFs), and the disrupted microtubules form neurofibrillary tangles (NFTs) that are the two prominent hallmark of AD leading to neurodegeneration (Drewes 2004).

MARK4 Evolution

The human kinome phylogenetic tree classifies the eukaryotic protein kinases (ePK) superfamily (428) into seven major groups that include 365 of ePK and rest 63 are grouped in the “other” category that are characteristically different from all the seven groups and do not fit into these groups. The human kinome includes: tyrosine kinase (TK); cyclic-nucleotide- and calcium/phospholipid-dependent kinases (AGC); calmodulin-dependent kinases (CAMK); CMGC group including CDK, MAPK, GSK, and CLK families; homologs of yeast sterile element (STE); tyrosine kinase-like (TKL); and casein kinase 1(CK1) (Hanks 2003). Furthermore, it has also been shown by phylogenetic analysis that MARK4 is evolutionarily strongly related to the orthologs in lower eukaryotic organism including Caenorhabditis elegans (Par-1) (Guo and Kemphues 1995), Drosophila melanogaster (dPAR-1) (Tomancak et al. 2000), and Schizosaccharomyces pombe (Kin 1) (Levin and Bishop 1990), thereby previously known as KIN1/PAR-1/MARK family (Tassan and Le Goff 2004). MARK belongs to the CAMK superfamily and is grouped under CAMK-like kinases (CAMKL) family (Kemphues 2000). MARK is one of the members of the 12 AMPK-related family of kinases (ARKs) belonging to AMP-activated kinases (AMPKs) subfamily (Manning et al. 2002) (Fig. 1).
Microtubule Affinity Regulating Kinase-4, Fig. 1

Evolutionary relationship of protein kinases (PKs). Ser/Thr PKs is classified into eight groups. MARK4 belongs to AMPK family, which is grouped under CAMKL family. (CAMK Calcium/calmodulin-dependent kinase, CAMKL CAMK Like kinase, AMPK Adenosine monophosphate kinases, MARK Microtubule affinity regulating kinases)

MARK possess four isoforms in human (Trinczek et al. 2004), MARK1–4 encoded on chromosomes 1, 11, 14, and 19, respectively (Tassan and Le Goff 2004). All the four isoforms of MARK are homologous to one another. These isoforms of MARK protein share a similar organization of the domain like all other AMPKs. The sequence similarity study has also shown that a 50% identity throughout the kinase domain of AMPKs and ARKs (Bright et al. 2009). Moreover, all the ARKs show a similar activation pattern like AMPK. Genetic studies of tissue-specific deletion of Liver kinase B1 (LKB1) or cells lacking LKB1 (He La cells) have revealed that LKB1 phosphorylates the Ser/Thr residue of all these kinases and activate them (Lizcano et al. 2004).

MARK4 Gene

The official symbol and full name of MARK4 is provided by HUGO gene nomenclature committee (HGNC: 13,538) (Gray et al. 2015). The Ensembl ID of the gene is ENSG00000007047 (Herrero et al. 2016). Its online Mendelian inheritance in man (OMIM) ID and Entrez ID is 606,495 and 57,787, respectively. The gene is located at chromosome 19.q13.32 on the forward strand and corresponds to a molecular mass of 375.15 kb. MARK4 gene maps to 45,079,288–45,305,283 Ensembl coordinates in Genome Reference Consortium of humans (GRch38). The gene has 66 orthologs and 12 paralogs (Herrero et al. 2016). It has a protein-coding gene that forms 11 splice variant transcripts that further encodes for multiple isoforms. MARK4 gene is a member of two Ensembl protein families, i.e., PTHR24346_SF22 and PTHR24346_SF23, which annotates to MARK4 (E.C.2.7.11) and probable Ser/Thr kinase MARKA (E.C.2.7.11) (Herrero et al. 2016). Annotation of this gene has been done by employing both automatic annotation from Ensembl and manual annotation using Havana (Havana ID: OTTHUMG00000181769). The annotated genes have been included in the collaborative consensus coding sequence (CCDS) project and have been given a unique identifier or version number as CCDS56097 and CCDS12658 in the human CCDS set which codes for MARK4L and MARK4S protein, respectively (Pruitt et al. 2009). The gene is also known to possess an overlapping locus, i.e., the exon of the locus overlaps exon of a read-through transcript or a transcript belonging to another locus. MARK4 also possess three related pseudogenes (Microtubule affinity regulating kinase 2 pseudogene 17-MARK2P17, MAP/microtubule affinity-regulating kinase 4 pseudogene-LOC100421505 and LOC100421504) located on both the long and short arm of chromosome 3 (Naz et al. 2013).

MARK4 Transcript

Out of the 11 transcripts, two of the transcripts code for protein belonging to MARK family, MARK4–001 (Transcript ID-ENST00000300843, Reference Sequence ID-NM_001199867) and MARK-002 (Transcript ID-ENST00000262891, Reference Sequence ID-NM_031417) that codes for MARK4L (Reference Sequence ID-NP_001186796) and MARK4S (Reference Sequence ID-NP_113605) (Herrero et al. 2016) (Fig. 2).
Microtubule Affinity Regulating Kinase-4, Fig. 2

MARK4 transcript. (a) MARK4–001 codes for MARK4L which possess 17 exons and has kinase-associated domain (KA1) at C-terminal. (b) MARK4–002 codes for MARK4S which possess 18 exons and the protein is truncated at C-terminal, difference from MARK4L, it has a domain at C-terminal which shows no homology with any known structure

MARK4–001: Alternate symbol of the transcript is given as AC005781.1–001. It is a member of Gencode basic gene set and maps to 45,251,258–45,303,693 in GRch38 Ensembl coordinates. Annotation of the transcript has been done using Havana (Havana ID-OTTHUMG00000181769). It is a member of human CCDS56097 set (Pruitt et al. 2009). It contains 17 exons and is annotated with 24 domains and features. The transcript shows 625 variations and maps to 41 oligo probes. MARK4–001 transcript is 3573 bp long which encodes 752 amino acids long MARK4L protein (Fig. 2a).

MARK4–002: Alternate symbol of the transcript is given as AC005781.1–002. It is a member of Gencode basic gene set and maps to 45,251,292–45,305,283 in GRch38 Ensembl coordinates. Annotation of the transcript has been done using Havana (Havana ID-OTTHUMG00000457538). It is a member of human CCDS12658 set (Pruitt et al. 2009). It contains 18 exons and is annotated with 19 domains and features. The transcript shows 589 variations and maps to 49 oligo probes. MARK4–002 transcript is 5209 bp long which encodes 688 amino acids long MARK4S protein (Fig. 2b).

MARK4 Protein

MARK4 is a member of Ser/Thr kinase (E.C.2.7.11.1) related to PAR-1 (Partitioning defective 1) that phosphorylates specific Ser/Thr residues of its substrate like Cdc 25, mitogens-activated protein kinase scaffolding protein KSR1, Tyrosine phosphatase PTPH1, plakophilin 2, MAPs, and regulates their activity (Zhang et al. 1997; Dequiedt et al. 2006; Naz et al. 2013). Due to alternative splicing of exon 16, there exists two isoforms of MARK4: MARK4L and MARK4S (Kato et al. 2001). The encoded proteins have different structure as well as expression levels (Beghini et al. 2003). MARK4L1/MARK4L is the long version or isoform of MARK4 which consist of 752 amino acids (approximately 82.5 kDa). This isoform is typically represented as MARK4. It lacks exon 16 and is characterized by the ELKL motif. They are normally expressed in progenitor cells and highest expression is found in brain and testis (Schneider et al. 2004). It colocalizes with the centrosome and MTs in the cultured cells (Trinczek et al. 2004). MARK4L1S/MARK4S is the short version of MARK4 which contains all the 18 exons but lacks KA1 domain at C-terminal, i.e., its C-terminal is truncated. The S-form possesses a unique domain which shows no homology with any known structure. It is made of 688 amino acids (approximately 75.3 kDa) and is found in brain and heart (Matenia and Mandelkow 2009).

Structure of MARK4 Protein

The protein has a molecular mass of 82.5 kDa and a theoretical pI of 9.73. MARK4 has 22 phenylalanine, five tryptophan, and 17 tyrosine residues and has an extinction coefficient of 53,705 M−1 cm−1 at 280 nm (http://www.uniprot.org). Both domain organization and crystal structure of MARK4 are explained below.

Domain organization: MARK4 share a similar structural organization of domains like AMPKs. It contains six domains, viz., N-terminal header, kinase domain, linker, UBA, spacer, and a kinase-associated domain (KA1) at C-terminal (Fig. 3). The N-lobe (P1-N58) is a minor smaller lobe made of five stranded β-sheets and a single α-helix (helix C). Till date, no function has been reported for this lobe (Marx et al. 2010). N-terminal header region is followed by the highly conserved catalytic kinase domain (KD: Y59-I310) like other Ser/Thr protein kinases (Johnson et al. 1996). It has a bilobal structure. The important functional unit of the KD includes the P-loop, the hinge region, T-loop (activation loop), and a C-loop (Catalytic loop). KD is connected to the Ubiquitin-binding domain (UBA) by a short stretch of residues called linker. Linker (N311-T323) is the most extended region and consists of glutamic acid and aspartic acid residues. It forms a negatively charged bulge at the bottom of kinase domain. UBA domain (E324-G368) is a small domain made of three α-helices: α1, α2, and α3. The first and the third α-helices are arranged in the antiparallel manner to each other forming the characteristic U-shape, contradictory to the other MARK isoforms in which typical N-shape is formed by these strands (Murphy et al. 2007). UBA domain is connected to the C-terminal by spacer (R369-G702). Spacer is the most variable region among all the MARK isoforms (Timm et al. 2008b). The C-terminal contains kinase-associated-1 domain (KA1) and is the most conserved region among all isoforms. It is predicted that KA1 domain contains amphipathic helices that are involved in protein–protein interactions.
Microtubule Affinity Regulating Kinase-4, Fig. 3

MARK4 protein domain organization. MARK4 is made up of 752 amino acids. It contains six different domains, viz., N-terminal header (1–58), kinase domain (KD,59–310), linker (311–323), ubiquitin-associated domain (UBA, 324–368), spacer domain (369–702), and kinase-associated domain (KA1,703–752) at C-terminal

Crystal structure: The crystal structure of MARK4 (KD-UBA) domain has been recently determined (Sack et al. 2016). It is predominantly an α-helical protein and contains 13 α-helices and 8 β-sheets (Fig. 4). The structure obtained shows great homology with all the other MARK isoforms.
Microtubule Affinity Regulating Kinase-4, Fig. 4

Structural representation of MARK4. KD (Y59-I310) is shown in blue color, UBA domain (E324-G368) is shown in pink color, and linker (N311-T323) which connects KD and UBA domain is shown in cyan color. Structure was drawn in PyMol using PDB code: 5ES1

Regulation of MARK4

MARK4 is regulated mainly by phosphorylation of Ser/Thr residues. Phosphorylation of the Thr214 in the T-loop or activation loop in the catalytic subunit by the upstream kinases like MARK kinase (MARKK)/Thousand and one amino acid (TAO-1) (Timm et al. 2003) and LKB1/Par-4 kinases (tumor suppressor kinases) (Lizcano et al. 2004) activates MARK4 (Bright et al. 2009). Phosphorylation at sites other than kinase domain either directly affects the activity or mediates its interaction with the regulatory proteins like 14–3-3 scaffold protein (Drewes 2004). MARK4 gets inhibited when the spacer domain gets phosphorylated by atypical kinase PK-C (Hurov et al. 2004; Naz et al. 2015a). When scaffolding proteins Par-5/14–3-3 or PAK5, which is a member of the p21 activated kinases family, binds to MARK4, its kinase activity gets inhibited (Matenia et al. 2005). It has also been shown that the phosphorylation of Ser218 residue by GSK-3β inhibits the kinase activity of the protein (Timm et al. 2008a). UBA domain autoregulates the kinase activity of MARK4, but it is still debatable (Jaleel et al. 2006) (Table 1).
Microtubule Affinity Regulating Kinase-4, Table 1

Regulation of MARK4 by kinases

S. No.

Kinases

Residue phosphorylated

Effect on MARK4

References

1.

MARKK/TAO-1

T408 and T214

Activation

(Matenia and Mandelkow 2009)

2.

LKB1

T408 and T14

Activation

(Kojima et al. 2007)

3.

CAMK1

T300

Activation

(Uboha et al. 2007)

4.

GSK-3β

S218

Inhibition

(Timm et al. 2008a)

5.

PAK-5

Binds with KD

Inhibition

(Timm et al. 2006)

6.

aPKC

T600

Inhibition

(Matenia and Mandelkow 2009)

7.

Adaptor protein (14–3-3)

Binds to spacer domain

Inhibition

(Matenia and Mandelkow 2009)

8.

PK-D

S400

Inhibition

(Watkins et al. 2008)

MARKK MARK Kinase, TAO-1 Thousand and one amino acids, LKB1 Liver kinase B1, CAMK1 Calcium/calmodulin-dependent kinase 1, GSK-3β Glycogen synthase kinase-3β, PAK-5 p21-activated kinases, aPKC Atypical protein kinase C, PK-D Protein kinase D

Functions of MARK4

MARK4 is involved in numerous functions such as cell polarity, cell signaling, and control of cell cycle (Matenia and Mandelkow 2009). It checks the transition of mitotic cell cycle from G1 to S-phase and from G2 to M-phase by regulating the length of cilia (Kuhns et al. 2013). As mentioned earlier, MARK4 is highly expressed in brain and testis. In brain, it regulates the microtubule dynamics and affects the cytoskeletal organization of the microtubules by phosphorylating the residues that are critical for binding of MAPs to MT (Trinczek et al. 2004). Furthermore, it is also involved in the MT-dependent transport (Mandelkow et al. 2004). The role of MARK4 in the testis is still unclear. Till now, it is only known that it maintains the polarity of spermatids during spermatogenesis (Tang et al. 2012). MARK4 also plays crucial role in energy homeostasis (PI3/Akt pathway) and Wnt-signaling pathway. MARK4 transcript is under the control of the transcription factor Tcf/LEF1 complex (Kato et al. 2001). Low expression of MARK4 blocks its function, executed under normal conditions. However, its overexpression leads pathogenesis of many diseases like metabolic syndrome (Met-S) including diet-induced obesity, type-II diabetes, cancer, and Alzheimer’s disease (Gabrovska et al. 2012; Feng et al. 2014).

Cilium biogenesis: The primary cilium is evolutionary conserved, membrane-bound, MT-based sensory organelle present on the surface of differentiated cells of almost all eukaryotes (D’Angelo and Franco 2009). Cilium biogenesis or ciliogenesis is initiated by the anchoring of basal bodies (a centriole-derived organelle) to the plasma membrane. The primary cilium is formed by axoneme at the mother centriole via intracellular pathway that gets activated by MARK4 (Kuhns et al. 2013). MARK4 couples with the basal body and initiate the extension of axoneme after the ciliary vesicles (CV) have docked the mother centriole (MC) (Nigg and Raff 2009).

MC contains a spike-like structure rich in electrons called as appendages at its distal and subdistal ends. A large number of appendage proteins like Cep164, ninein, ODF2 (outer dense fiber protein 2 or cenexin), and centriolin help in cilia assembly (Graser et al. 2007; Ishikawa and Marshall 2011). Cep164 dock the CV at the mother centriole and promotes its association with the distal appendages with the help of a small GTPase, Rab8a, and its guanine-nucleotide exchange factor (GEF), Rabin8a (Schmidt et al. 2012). The elongation of axoneme continues until the membrane-bound axoneme reaches the cell surface and fuses with the plasma membrane, allowing the cilium to be exposed to the extracellular medium (Sung and Leroux 2013).

In case of cell undergoing cycling, CP110, a negative regulator of cilia formation along with its partner Cep97 is confined to the distal ends of both MC and daughter centrioles. CP110-Cep97 forms a cap-like structure above the growing cilia and blocks its extension (Schmidt et al. 2009). This interaction is supported by Kif24 (Kobayashi et al. 2011). Before ciliogenesis, this complex needs to be removed from the mother centriole (Spektor et al. 2007). MARK4 is one of the kinases that phosphorylate ODF2, promotes its accumulation at MC and stabilizes the complex formed between ODF2 and centriolar components (Nigg and Raff 2009; Kuhns et al. 2013). This in turn removes CP110-Cep97 complex from the distal end of the MC and favors axoneme extension by allowing the attachment of basal body with CV (Fig. 5). Low level of MARK4 in the cell impairs axoneme extension, and ciliogenesis as CP110-Cep97 complex could not be eliminated from the MC (Kuhns et al. 2013).
Microtubule Affinity Regulating Kinase-4, Fig. 5

MARK4 in the cilium biogenesis. MARK4 phosphorylates ODF2. After phosphorylation the complex get removed from mother centriole and elongation of axoneme takes place. This is how MARK4 favors formation of cilia

Microtubule-dependent transport: The intracellular transport of vesicles and organelles through cytoplasm, endocytosis or exocytosis of vesicles, distribution of organelles like mitochondria or peroxisomes, transport of protein aggregates to centrosome for formation of aggresome are executed by motor proteins (MP), kinesin and dyenin which show a microtubule-dependent transport (Terada and Hirokawa 2000). These MP form the polar MT network that forms the track for the transport. The MT tracks are covered by MAPs that provide stability to them to gain a particular cell shape (Baas 2002). Meanwhile, these MAPs also compete with MP to bind on the MT (Hagiwara et al. 1994). Eventually, the microtubule-dependent transport is restrained. In case of neurons, the flux of organelles down the axon gets disturbed (Stamer et al. 2002).

MARK4 phosphorylates MAPs like tau in neurons due to which they detach from MTs. As soon as they dissociate from MT, the polar track gets cleared and extended which facilitates the trafficking of organelles like lysosome, mitochondria, and vesicles like VSV-G vesicles and clathrin-coated vesicles (Mandelkow et al. 2004) (Fig. 6). MARK4 increases the run-length by removing MAPs off the MT track, and organelles move freely in the forward direction without changing their instantaneous velocities. Thus, MARK4 relieves transport inhibition posed by MAPs. The microtubule-dependent transport is blocked if there is loss of MARK4 in the cell.
Microtubule Affinity Regulating Kinase-4, Fig. 6

MARK4 helps in microtubule dependent transport. MARK4 phosphorylates MAPs. Phosphorylated MAPs detaches from MT, hence clearing the polar microtubular track for the transport of vesicles and organelles

Microtubule dynamics: MTs are the cytoskeletal polar structure that help in division of cell, maintaining cell structure, cell signaling, and intracellular transport (Etienne-Manneville 2010). They are made of 13 protofilaments and each one is formed from α-β tubulin dimer. Microtubule dynamics is the intrinsic property of the MT building block to form α-β tubulin dimer. α-tubulin is present at the “minus (−)” end and β-tubulin is present at the “plus (+)” end where it hydrolyzes GTP and derive energy for MT assembly. MT dynamic stability is controlled by MAPs. The bound MAPs provide stability and increase the rate of assembly and growth continues at the end of MT, thereby altering the microtubule dynamics (Lodish et al. 2000). MAPs after getting phosphorylated by MARK4 could not bind to the MT resulting in dissociation of tubulin subunits and depolymerization. Thus, the length of MTs can be regulated by phosphorylation of MAPs. Reduced expression of MARK4 results in an increased rate of microtubule assembly that leads to disruption of normal geometry of mitotic spindle fibers and causes instability of chromosomes as seen in case of colorectal cancer cells (Ertych et al. 2014).

Cell polarization: MARK4 establishes and maintains cell polarity in cells like neuronal cells and spermatids by regulating the function of MAPs through phosphorylation as done by PAR-gene (partitioning gene) products (Marx et al. 2010). MARK4 is found at the basal region of cells, where it induces apico-basal polarity during cellular processes as in case of development of embryos. This explains its importance in cell polarity (Kemphues 2000).

Binding of MAPs like tau, MAP2, and MAP4 to MT is modulated by the phosphorylation in a spatiotemporal fashion. MARK4 expressed in brain cells phosphorylates MAPs on their tubulin-binding repeats. This leads to local microtubule instability that results in differentiation of neuroblastoma cells. Neurite outgrowth takes place on these cells that establishes neuronal polarity (Biernat et al. 2002).

MTs are used as the polar track for spermatids to traffic across the epithelium. Myosin VIIa is the motor protein which helps in transporting up and down the epithelium until mature spermatids detach from epithelium at spermiation. Cell polarity proteins such as Par-6, MARK4, and the scribble-based protein complex have been located in the testis specifically in the sertoli and germ cells, conspicuously in spermatid. MARK4 and Par-6 work in a coordinated fashion to establish spermatid polarity during the seminiferous epithelial cycle of spermatogenesis.

MARK4 exhibits a spatial and temporal form of expression and is identified at the apical ectoplasmic specialization (ES), at tight junctions (TJ), and beneath TJs (Tang et al. 2012). Expression of MARK4 in testis maintains the changes in the structure of both the apical and basal ES during spermatogenesis. The restructuring of ES that as a result maintains its integrity is important for the establishment and maintenance of polarity in the elongating spermatids, which interacts with the tubulin-cytoskeleton network and attaches with the sertoli cells (Tang et al. 2012). In stage IV–VI of the seminiferous epithelial cycle, MARK4 surrounds the complete head of the developing spermatids. Later in stage VII tubules, it is restricted only on concave side of the elongated spermatid head and it gets dispersed to the entire tip of spermatid head, inducing polarity in spermatids and fastly decreases by stage VIII. MARK4 interacts with α-tubulin and the desmosomal armadillo protein plakophilin-2 at the blood-testis barrier (BTB) to maintain the integrity of apical ES and restructures BTB during spermatogenesis.

It is also suggested that phosphorylation of MARK4 by aPKC also results in cell polarity in testis (Wong et al. 2009). Binding sites for 14–3-3 scaffold-binding protein is created on MARK4 due to this phosphorylation. 14–3-3 protein regulates cell adhesion at the apical ES and at BTB in testis to facilitate preleptotene spermatocyte transit thus establishes polarity in spermatids.

Loss of MARK4 at apical ES results in its disruption due to which the elongated spermatid detaches from the epithelium. It causes the premature release of spermatids from the epithelium (Tang et al. 2012).

Role in Diseases

Cancer: MARK4 plays an important role in the cell cycle regulation. It causes prostate cancer which is the second highest cause of death in men, and is ubiquitously expressed in many other cancers including hepatocarcinoma (Kato et al. 2001), leukemia, breast cancer (Brennan and Brown 2004), and gliomas (Magnani et al. 2011). Array-comparative genomic hybridization (CGH) studies of 25 primary glioma cell lines have shown that the amplification of chromosome 19.q.13 results in formation of gliomas from a glial-restricted progenitor in brains (Hartmann et al. 2002). MARK4 is involved in the Wnt signaling pathway (acronym for Drosophila melanogaster wingless gene) which is upregulated in these cancers due to high expression of MARK4 (Gabrovska et al. 2012) (Fig. 7). This inhibits the degradation of β-catenin which enters into nucleus and binds to TCF/LEF (T-cell factor/Lymphoid enhancing factor) and increases its transcription activity (Yu et al. 2011).
Microtubule Affinity Regulating Kinase-4, Fig. 7

MARK4 plays an important role in Wnt signaling involved in cancer. Wnt as a ligand binds to frizzled receptor in association with LRP5/6 receptor. This signals breakdown of destruction complex. In response to this, Dishevelled protein (Dsh) gets phosphorylated by MARK4 and CK1. Unphosphorylated β-catenin accumulates in cytoplasm which is translocated into the nucleus. It consequently increases TCF/LEF-based transcription, leading to overexpression of MARK4, MMP7, and c-myc that deregulates cell cycle leading to development of cancer

Increased expression of MARK4 opens the door for the binding of Wnt protein to the N-terminal extra cellular cysteine-rich domain of a Frizzled (Fz) family receptor (Wodarz and Nusse 1998). To facilitate this binding and signaling, coreceptors like lipoprotein-related receptor (LRP)-5/6, receptor tyrosine kinase (RTK), and receptor tyrosine kinase-like orphan receptor 2 (ROR2) are translocated to the plasma membrane (He et al. 2004) leading to the disruption of the destruction complex (Axin, APC, Protein phosphatase 2, GSK-3, and CK-1) which is translocated to the plasma membrane where it is phosphorylated by other proteins that aids in binding of Axin to the cytoplasmic tail of LRP-5/6. On binding to the receptor Axin is dephosphorylated and its stability and concentration are decreased. This signals the phosphorylation of phosphoprotein dishevelled (Dsh) by MARK4 and it gets activated (Kinzler and Vogelstein 1996). The DIX and PDZ domains of Dsh protein inhibit the GSK-3 activity of the destruction complex. This allows β-catenin to accumulate and localize to the nucleus and subsequently induce a cellular response via gene transduction alongside the TCF/LEF transcription factors and results in uncontrolled cell growth and turn the normal healthy cell into cancerous. MARK4 is currently considered as a potential drug target for all these associated diseases (Naz et al. 2015b, c).

Neurodegenerative disorders: MARKs regulate the interaction of MAPs with microtubules. MARK phosphorylates serine residue at KXGS motif of MAPs (tau, MAP2, and MAP4), and the binding ability of MAPs to the microtubule is reduced (Dehmelt and Halpain 2005). Overexpression of MARK4 leads to microtubule disassembly and disruption of the cellular microtubule network increasing microtubule dynamics thereby disturbing many of the cellular processes and sometime cell death also (Ebneth et al. 1999). Moreover, it has also been observed that overexpression of MARK in rat hippocampal neurons lead to hyper phosphorylation of tau protein (Yu et al. 2012). This causes defect in synapses and dendritic spines which are characteristics of many tauopathies and neurodegenerative disorders. In neuronal axons, MARK phosphorylates serine in tau, specifically S262 is hyper phosphorylated followed by aggregation to paired helical filaments (PHFs) that results in formation of neurofibrillary tangles and degeneration of neurons (Grundke-Iqbal et al. 1986) (Fig. 8). These consequences mark the onset of neurodegenerative diseases like Alzheimer’s diseases. It has been found that the tau purified from neurofibrillary tangles doesn’t bind to microtubules but if dephosphorylated then they gain their binding ability.
Microtubule Affinity Regulating Kinase-4, Fig. 8

MARK4 in neurodegenerative diseases. MARK4 phopshorylates tau at Ser262 which results in their detachment from MTs. This result in destabilization of MTs. Further, tau is hyperphosphorylated by other kinases at MT-binding domain that results in formation of paired helical fragments and neurofibrillary tangles. These are the two hallmarks of Alzheimer’s disease

Metabolic disorders: It has been found that dysregulation in the activity of AMPKs leads to metabolic syndrome which induces obesity, type-II diabetes, and cardiovascular diseases. The metabolic disorders, type-II diabetes, and obesity are interlinked (Sun et al. 2012). There exist a strong correlation between insulin resistance and increased lipid availability in the tissue. This correlation has been justified from many studies involving obese people and animal models. When the cell experiences energy starvation then AMPK gets activated by phosphorylation at T172 in the activation loop by upstream kinase, specifically LKB-1 (a primary kinase of 50-kDa having Ser/Thr kinase activity) (Sanders et al. 2007). As soon as phosphorylation takes place, other kinases belonging to AMPK subfamily like MARKs, NuaKs, and BRSK also gets activated (Manning et al. 2002). Any defects in PKB/Akt pathway or AMPK function reduces glucose uptake and hepatic deletion results in glucose intolerance, insulin resistance, and diet-induced obesity. It has also been found that MARK4 acts as a negative regulator of mTORC-1 and inhibits the PKB/Akt pathway. Increased expression of MARK4 decreases the rate of phosphorylation of S6 K and inhibits protein synthesis (Li and Guan 2013). In response to energy stress condition, MARK4 also phosphorylates serine residues of raptor (Regulatory associated protein of mTOR) which becomes a substrate for 14–3-3 scaffold protein. This association further inhibits mTORC-1 kinase activity. Thus, MARK4 blocks amino acids, glucose, and insulin induced mTORC-1 activation and results in a large number of metabolic disorders.

Summary

MARK4 belongs to the serine/threonine kinases family encoded by MARK4 gene located on the chromosome 19. This kinase family was formerly known as KIN1/PAR1/MARK family showing the conserved evolutionary relationship with yeast and nematode. Due to alternative splicing of exon 16 in the MARK4 transcript, there exist two different isoforms of the protein, viz., MARK4S and MARK4L. MARK4 is highly expressed in brain and testis where it phosphorylates MAPs and regulates many important cellular processes like cell polarity, growth and stabilization of MTs, and transport of vesicles via MT polar track. It has also been found that MARK4 acts as a negative regulator of mTORC1. Therefore, MARK4 can be considered as a potential therapeutic target in treating major diseases like cancers and metabolic syndromes. There is a need to identify promising therapeutic agents which have better efficiency to impede the pathogenesis induced by MARK4.

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Authors and Affiliations

  1. 1.Centre for Interdisciplinary Research in Basic SciencesJamia Millia IslamiaNew DelhiIndia