MARK4

Summary

MARK4 (microtubule affinity regulating kinase 4, HGNC:13538) is a protein-coding gene on chromosome 19q13.32, encoding MAP/microtubule affinity-regulating kinase 4 (Q96L34). Serine/threonine-protein kinase.

This gene encodes a member of the microtubule affinity-regulating kinase family. These protein kinases phosphorylate microtubule-associated proteins and regulate the transition between stable and dynamic microtubules. The encoded protein is associated with the centrosome throughout mitosis and may be involved in cell cycle control. Expression of this gene is a potential marker for cancer, and the encoded protein may also play a role in Alzheimer’s disease. Pseudogenes of this gene are located on both the short and long arm of chromosome 3. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene.

Source: NCBI Gene 57787 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neurodevelopmental disorder (Limited, GenCC)
• GWAS associations: 59
• Clinical variants (ClinVar): 119 total
• Druggable target: yes — 22 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_001199867

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:13538
Approved symbol	MARK4
Name	microtubule affinity regulating kinase 4
Location	19q13.32
Locus type	gene with protein product
Status	Approved
Aliases	Nbla00650, FLJ90097, KIAA1860, PAR-1D
Ensembl gene	ENSG00000007047
Ensembl biotype	protein_coding
OMIM	606495
Entrez	57787

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 6 protein_coding, 3 retained_intron, 2 nonsense_mediated_decay

ENST00000262891, ENST00000300843, ENST00000587566, ENST00000588533, ENST00000588621, ENST00000590897, ENST00000590909, ENST00000592207, ENST00000592762, ENST00000866200, ENST00000925282

RefSeq mRNA: 2 — MANE Select: NM_001199867 NM_001199867, NM_031417

CCDS: CCDS12658, CCDS56097

Canonical transcript exons

ENST00000262891 — 17 exons

Exon	Start	End
ENSE00000712853	45294349	45294452
ENSE00000861608	45297676	45297954
ENSE00002767256	45251271	45251639
ENSE00002906353	45302374	45305284
ENSE00003473034	45263319	45263367
ENSE00003491154	45264684	45264749
ENSE00003501954	45263113	45263166
ENSE00003516964	45264840	45264910
ENSE00003520915	45287447	45287664
ENSE00003522993	45278516	45278615
ENSE00003527944	45280575	45280734
ENSE00003612930	45277923	45278042
ENSE00003642901	45271472	45271708
ENSE00003658059	45280374	45280483
ENSE00003659975	45258989	45259189
ENSE00003691658	45299811	45299855
ENSE00003789080	45266225	45266281

Expression profiles

Bgee: expression breadth ubiquitous, 285 present calls, max score 96.99.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 14.8082 / max 130.8986, expressed in 1795 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
176394	14.3668	1795
176381	11.5652	1777
176396	0.1619	48
176395	0.1546	47
176397	0.1248	34

Top tissues by expression

291 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
cortical plate	UBERON:0005343	96.99	gold quality
cervix squamous epithelium	UBERON:0006922	95.99	gold quality
lateral nuclear group of thalamus	UBERON:0002736	95.37	gold quality
ganglionic eminence	UBERON:0004023	95.22	gold quality
prefrontal cortex	UBERON:0000451	95.03	gold quality
parotid gland	UBERON:0001831	94.95	gold quality
CA1 field of hippocampus	UBERON:0003881	94.80	gold quality
stromal cell of endometrium	CL:0002255	94.57	gold quality
right testis	UBERON:0004534	94.28	gold quality
left testis	UBERON:0004533	93.95	gold quality
endothelial cell	CL:0000115	93.85	gold quality
frontal cortex	UBERON:0001870	93.57	gold quality
neocortex	UBERON:0001950	93.36	gold quality
putamen	UBERON:0001874	93.34	gold quality
nucleus accumbens	UBERON:0001882	93.30	gold quality
olfactory bulb	UBERON:0002264	93.27	silver quality
cingulate cortex	UBERON:0003027	93.21	gold quality
anterior cingulate cortex	UBERON:0009835	93.21	gold quality
entorhinal cortex	UBERON:0002728	93.16	gold quality
hair follicle	UBERON:0002073	93.09	gold quality
caudate nucleus	UBERON:0001873	92.94	gold quality
right frontal lobe	UBERON:0002810	92.87	gold quality
cerebral cortex	UBERON:0000956	92.63	gold quality
ventricular zone	UBERON:0003053	92.55	gold quality
telencephalon	UBERON:0001893	92.49	gold quality
lateral globus pallidus	UBERON:0002476	92.49	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	92.36	gold quality
testis	UBERON:0000473	92.33	gold quality
Brodmann (1909) area 9	UBERON:0013540	92.08	gold quality
forebrain	UBERON:0001890	92.01	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-MTAB-6386	no	8.90
E-ANND-3	no	4.17

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CTNNB1

miRNA regulators (miRDB)

89 targeting MARK4, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3925-3P	100.00	69.95	1237
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-345-3P	99.89	70.23	1421
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-3681-3P	99.88	70.46	2254
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-544A	99.84	68.66	1965
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-1273H-5P	99.77	66.32	2471
HSA-MIR-4319	99.76	69.83	2586
HSA-MIR-6763-5P	99.76	64.68	1767
HSA-MIR-6752-3P	99.72	66.71	1587
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-1825	99.72	68.11	1089
HSA-MIR-30B-3P	99.70	65.76	2325
HSA-MIR-3689A-3P	99.70	65.73	2306
HSA-MIR-3689B-3P	99.70	65.71	2311
HSA-MIR-3689C	99.70	65.71	2311
HSA-MIR-6779-5P	99.70	65.76	2363
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-4530	99.69	66.47	1509
HSA-MIR-6887-3P	99.66	67.83	1778
HSA-MIR-3158-5P	99.65	67.51	1763
HSA-MIR-10394-5P	99.65	66.83	1852
HSA-MIR-1205	99.65	66.76	1826

Literature-anchored findings (GeneRIF, showing 27)

• Normally expressed in neural progenitors, re-expressed in gliomas and may become a target of amplification upon chr. 19 rearrangement. (PMID:12735302)
• MARK4 is likely to be directly involved in microtubule organization in neuronal cells (PMID:14594945)
• NUAK1 and MARK4 are substrates of USP9X (PMID:18254724)
• demonstrated that the endogenous MARK4L colocalizes with centrosomes at all mitotic stages and resides in centrosome-enriched fractions. (PMID:19759416)
• The balance between the MARK4 isoforms is carefully guarded during neural differentiation but may be subverted in gliomagenesis. (PMID:22156016)
• Even though an association of the polymorphisms rs2850328 and rs2395 and breast cancer was not detected in our case-control study population, other variants within the PPP3CA and MARK4 genes may still be associated with breast cancer. (PMID:22506312)
• MARK4 is a new negative regulator of mTORC1 (PMID:23184942)
• MARK4 is a critical positive regulator of early steps in ciliogenesis. (PMID:23400999)
• A strong and significant elevation of MARK4 expression and MARK4-tau interactions in AD brains correlates with the Braak stages of the disease, suggesting that the MARK4-tau interactions are of functional importance in the progression of AD. (PMID:23666762)
• Molecular dynamic simulation data predicted the three dimensional structure for the kinase domain of MARK4 and its structural properties. (PMID:24763618)
• MARK4 is a key component in the regulation of microtubule dynamics and has major role in cell cycle progression, particularly at the G1/S transition. (PMID:25123532)
• Suggest role for polypyrimidine-tract binding protein in regulating alternative splicing of MARK4 in gliomas. (PMID:25578778)
• Atypical PKC phosphorylates serine-threonine residues of MARK4. (PMID:26346160)
• data demonstrate that miR-515-5p dramatically inhibits cell migration by directly down-regulating MARK4 expression in two different cancer types (PMID:26882547)
• Our results show that MARK4 acts as a negative regulator of the Hippo kinase cassette to promote YAP/TAZ activity and that loss of MARK4 restrains the tumorigenic properties of breast cancer cells. (PMID:28183853)
• MARK4-dependent NLRP3 inflammasome activation in the hematopoietic cells regulates the development of atherosclerosis. (PMID:31167564)
• Reduced expression of MARK4 protein in ovulatory polycystic ovarian syndrome increases the risk of hyperlipidemia, hyperandrogenism and metabolic syndrome. (PMID:31322078)
• Structure and dynamics of inactive and active MARK4: conformational switching through the activation process. (PMID:31411112)
• MARK4 expression is upregulated by LINC00673 in breast cancer cells. (PMID:31623640)
• Impact of glioblastoma multiforme associated mutations on the structure and function of MAP/microtubule affinity regulating kinase 4. (PMID:32141394)
• Structural and biochemical investigation of MARK4 inhibitory potential of cholic acid: Towards therapeutic implications in neurodegenerative diseases. (PMID:32535203)
• Microtubule affinity-regulating kinase 4 with an Alzheimer’s disease-related mutation promotes tau accumulation and exacerbates neurodegeneration. (PMID:33020179)
• Myricetin inhibits breast and lung cancer cells proliferation via inhibiting MARK4. (PMID:34751461)
• MARK2/4 promotes Warburg effect and cell growth in non-small cell lung carcinoma through the AMPKalpha1/mTOR/HIF-1alpha signaling pathway. (PMID:35192892)
• Gain-of-function MARK4 variant associates with pediatric neurodevelopmental disorder and dysmorphism. (PMID:38041405)
• Interaction of Sp1 and Setd8 promotes vascular smooth muscle cells apoptosis by activating Mark4 in vascular calcification. (PMID:38301049)
• MARK4 promotes the malignant phenotype of gastric cancer through the MAPK/ERK signaling pathway. (PMID:39079384)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	mark4a	ENSDARG00000023914
danio_rerio	mark4b	ENSDARG00000024966
mus_musculus	Mark4	ENSMUSG00000030397
rattus_norvegicus	Mark4	ENSRNOG00000017069

Paralogs (3): MARK2 (ENSG00000072518), MARK3 (ENSG00000075413), MARK1 (ENSG00000116141)

Protein

Protein identifiers

MAP/microtubule affinity-regulating kinase 4 — Q96L34 (reviewed: Q96L34)

Alternative names: MAP/microtubule affinity-regulating kinase-like 1

All UniProt accessions (5): Q96L34, K7EK17, K7EKG8, K7EN95, Q6IPE9

UniProt curated annotations — full annotation on UniProt →

Function. Serine/threonine-protein kinase. Phosphorylates the microtubule-associated protein MAPT/TAU. Also phosphorylates the microtubule-associated proteins MAP2 and MAP4. Involved in regulation of the microtubule network, causing reorganization of microtubules into bundles. Required for the initiation of axoneme extension during cilium assembly. Regulates the centrosomal location of ODF2 and phosphorylates ODF2 in vitro. Plays a role in cell cycle progression, specifically in the G1/S checkpoint. Reduces neuronal cell survival. Plays a role in energy homeostasis by regulating satiety and metabolic rate. Promotes adipogenesis by activating JNK1 and inhibiting the p38MAPK pathway, and triggers apoptosis by activating the JNK1 pathway. Phosphorylates mTORC1 complex member RPTOR and acts as a negative regulator of the mTORC1 complex, probably due to disruption of the interaction between phosphorylated RPTOR and the RRAGA/RRAGC heterodimer which is required for mTORC1 activation. Involved in NLRP3 positioning along microtubules by mediating NLRP3 recruitment to microtubule organizing center (MTOC) upon inflammasome activation.

Subunit / interactions. Interacts with MAPT/TAU. Interacts with gamma-tubulin. Interacts with ODF2. Interacts with USP9X. Interacts with YWHAQ. Interacts with NLRP3; promoting NLRP3 recruitment to microtubule organizing center (MTOC).

Subcellular location. Cytoplasm. Cytoskeleton. Microtubule organizing center. Centrosome. Cilium basal body. Cilium axoneme. Cell projection. Dendrite.

Tissue specificity. Ubiquitous. Isoform 2 is brain-specific. Expressed at highest levels in brain and testis. Also expressed in heart, lung, liver, muscle, kidney and spleen.

Post-translational modifications. Ubiquitinated with ‘Lys-29’- and ‘Lys-33’-linked polyubiquitins which appear to impede LKB1-mediated phosphorylation. Deubiquitinated by USP9X. Phosphorylated at Thr-214 by STK11/LKB1 in complex with STE20-related adapter-alpha (STRADA) pseudo kinase and CAB39. Phosphorylated throughout the cell cycle.

Activity regulation. Activated by phosphorylation on Thr-214.

Similarity. Belongs to the protein kinase superfamily. CAMK Ser/Thr protein kinase family. SNF1 subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
Q96L34-1	1, MARK4L	yes
Q96L34-2	2, MARKL1S, MARK4S

RefSeq proteins (2): NP_001186796, NP_113605 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000719	Prot_kinase_dom	Domain
IPR001772	KA1_dom	Domain
IPR008271	Ser/Thr_kinase_AS	Active_site
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR015940	UBA	Domain
IPR017441	Protein_kinase_ATP_BS	Binding_site
IPR028375	KA1/Ssp2_C	Homologous_superfamily
IPR049508	MARK1-4_cat	Domain

Pfam: PF00069, PF00627, PF02149

Catalyzed reactions (Rhea), 2 shown:

• L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H(+) (RHEA:17989)
• L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H(+) (RHEA:46608)

UniProt features (47 total): helix 13, strand 7, turn 6, domain 3, modified residue 3, binding site 2, sequence variant 2, mutagenesis site 2, sequence conflict 2, region of interest 2, compositionally biased region 2, chain 1, splice variant 1, active site 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
5ES1	X-RAY DIFFRACTION	2.8
8XFL	X-RAY DIFFRACTION	3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96L34-F1	67.97	0.38

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 181 (proton acceptor)

Ligand- & substrate-binding residues (2): 88; 65–73

Post-translational modifications (3): 214, 423, 543

Mutagenesis-validated functional residues (2):

Position	Phenotype
214	prevents phosphorylation and activation by stk11/lkb1 complex.
214	mimicks phosphorylation state, leading to increased activity. decreases mtorc1 activity.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-5620912	Anchoring of the basal body to the plasma membrane
R-HSA-1852241	Organelle biogenesis and maintenance
R-HSA-5617833	Cilium Assembly

MSigDB gene sets: 214 (showing top): GOBP_PROTEIN_LOCALIZATION_TO_CYTOSKELETON, GOBP_REGULATION_OF_MICROTUBULE_BASED_PROCESS, GCM_GSPT1, GOBP_INFLAMMATORY_RESPONSE, ROVERSI_GLIOMA_COPY_NUMBER_UP, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GOBP_POSITIVE_REGULATION_OF_PROTEIN_LOCALIZATION, GOBP_POSITIVE_REGULATION_OF_ORGANELLE_ORGANIZATION, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, GOCC_MICROTUBULE_ORGANIZING_CENTER, GOBP_POSITIVE_REGULATION_OF_RESPONSE_TO_EXTERNAL_STIMULUS, GOBP_REGULATION_OF_IMMUNE_RESPONSE, GOBP_POSITIVE_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, GOBP_REGULATION_OF_CELL_PROJECTION_ORGANIZATION, AP1_Q4_01

GO Biological Process (16): microtubule cytoskeleton organization (GO:0000226), microtubule bundle formation (GO:0001578), protein phosphorylation (GO:0006468), nervous system development (GO:0007399), intracellular signal transduction (GO:0035556), positive regulation of programmed cell death (GO:0043068), cilium organization (GO:0044782), positive regulation of cilium assembly (GO:0045724), positive regulation of cell cycle (GO:0045787), regulation of centrosome cycle (GO:0046605), cell division (GO:0051301), positive regulation of NLRP3 inflammasome complex assembly (GO:1900227), positive regulation of protein localization to centrosome (GO:1904781), cell projection organization (GO:0030030), microtubule polymerization (GO:0046785), cilium disassembly (GO:0061523)

GO Molecular Function (14): protein serine/threonine kinase activity (GO:0004674), ATP binding (GO:0005524), microtubule binding (GO:0008017), cytoskeletal adaptor activity (GO:0008093), gamma-tubulin binding (GO:0043015), ubiquitin binding (GO:0043130), tau protein binding (GO:0048156), tau-protein kinase activity (GO:0050321), protein serine kinase activity (GO:0106310), nucleotide binding (GO:0000166), protein kinase activity (GO:0004672), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740)

GO Cellular Component (13): gamma-tubulin complex (GO:0000930), cytoplasm (GO:0005737), centrosome (GO:0005813), microtubule organizing center (GO:0005815), cytosol (GO:0005829), axoneme (GO:0005930), microtubule cytoskeleton (GO:0015630), dendrite (GO:0030425), midbody (GO:0030496), ciliary basal body (GO:0036064), neuron projection (GO:0043005), cytoskeleton (GO:0005856), cell projection (GO:0042995)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Assembly of the 9+0 primary cilium	1
Organelle biogenesis and maintenance	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	6
microtubule organizing center	3
intracellular anatomical structure	2
positive regulation of cellular process	2
protein kinase activity	2
tubulin binding	2
cytoskeletal protein binding	2
cytoskeleton	2
cytoskeleton organization	1
microtubule-based process	1
microtubule cytoskeleton organization	1
phosphorylation	1
protein modification process	1
system development	1
signal transduction	1
programmed cell death	1
regulation of programmed cell death	1
organelle organization	1
plasma membrane bounded cell projection organization	1
cilium assembly	1
positive regulation of plasma membrane bounded cell projection assembly	1
regulation of cilium assembly	1
positive regulation of organelle assembly	1
cell cycle	1
regulation of cell cycle	1
centrosome cycle	1
regulation of cell cycle process	1
regulation of microtubule-based process	1
regulation of cellular component organization	1
cellular process	1
positive regulation of protein-containing complex assembly	1
NLRP3 inflammasome complex assembly	1
positive regulation of inflammasome-mediated signaling pathway	1
regulation of NLRP3 inflammasome complex assembly	1
protein localization to centrosome	1
positive regulation of protein localization	1
regulation of protein localization to centrosome	1
cellular component organization	1
microtubule nucleation	1
microtubule polymerization or depolymerization	1

Protein interactions and networks

STRING

908 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MARK4	GRIK4	Q16099	865
MARK4	USP9X	Q93008	770
MARK4	EXOC3L2	Q2M3D2	609
MARK4	BLOC1S3	Q6QNY0	608
MARK4	NLRP3	Q96P20	560
MARK4	ARHGEF2	Q92974	534
MARK4	APP	P05067	513
MARK4	AXIN1	O15169	509
MARK4	CEP97	Q8IW35	449
MARK4	MAP4	P27816	430
MARK4	BIN1	O00499	427
MARK4	AGAP2	Q99490	409
MARK4	PICALM	Q13492	389
MARK4	MAPT	P10636	379
MARK4	CCP110	O43303	370

IntAct

62 interactions, top by confidence:

A	B	Type	Score
MARK4	YWHAH	psi-mi:“MI:0915”(physical association)	0.720
YWHAH	MARK4	psi-mi:“MI:0915”(physical association)	0.720
YWHAG	BLTP3B	psi-mi:“MI:0914”(association)	0.640
MARK4	TUBG1	psi-mi:“MI:0915”(physical association)	0.620
TUBG1	MARK4	psi-mi:“MI:0915”(physical association)	0.620
YWHAH	BLTP3B	psi-mi:“MI:0914”(association)	0.570
MARK4	KRT31	psi-mi:“MI:0915”(physical association)	0.560
KRT31	MARK4	psi-mi:“MI:0915”(physical association)	0.560
APLP2	MARK4	psi-mi:“MI:0915”(physical association)	0.560
CSNK1D	MARK4	psi-mi:“MI:0915”(physical association)	0.560
MARK4	LYN	psi-mi:“MI:0915”(physical association)	0.560
APP	MARK4	psi-mi:“MI:0915”(physical association)	0.560
STK11	MARK4	psi-mi:“MI:0217”(phosphorylation reaction)	0.540
MARK4	STK11	psi-mi:“MI:0915”(physical association)	0.540
MARK4	YWHAE	psi-mi:“MI:0914”(association)	0.530
YWHAZ	BLTP3B	psi-mi:“MI:0914”(association)	0.530
MANSC1	KLRG2	psi-mi:“MI:0914”(association)	0.530
SLC31A1	C2orf72	psi-mi:“MI:0914”(association)	0.530
PNMA2	CCDC85C	psi-mi:“MI:0914”(association)	0.530

BioGRID (96): MARK4 (Two-hybrid), MARK4 (Two-hybrid), MARK4 (Two-hybrid), MARK4 (Two-hybrid), KRT40 (Two-hybrid), NOTCH2NL (Two-hybrid), MARK4 (Protein-RNA), MARK4 (Biochemical Activity), RPIA (Affinity Capture-MS), MARK4 (Affinity Capture-MS), MARK4 (Affinity Capture-MS), MARK4 (Affinity Capture-RNA), MYH9 (Affinity Capture-MS), MYH10 (Affinity Capture-MS), HSPA4 (Affinity Capture-MS)

ESM2 similar proteins: A0AUV4, A1A5Q6, A1A5R7, A2KF29, B1WAS2, C0HKC8, C0HKC9, D3ZML2, O60285, O74536, O88831, O88866, P41279, P51956, P57058, P97756, Q20443, Q2T9U5, Q5R7G9, Q5XHI9, Q60670, Q63562, Q641K5, Q66HE5, Q68UT7, Q6P431, Q6VZ17, Q7T0B0, Q7T0B1, Q7TNJ7, Q7TNL4, Q8BHI9, Q8BZN4, Q8C078, Q8C0N0, Q8C0V7, Q8C0X8, Q8CIP4, Q8IY84, Q8K4K4

Diamond homologs: A0AUV4, A1A5Q6, A2KF29, A2XFF4, A8WYE4, B2DD29, B7XHR6, B8BBT7, C0HKC8, C0HKC9, F1QGZ6, O08678, O08679, O22932, O22971, O65554, O74536, O94168, P27448, P52497, P54645, P54646, P57059, P92958, Q00372, Q02723, Q03141, Q05512, Q09137, Q0D4B2, Q0JI49, Q13131, Q19469, Q28948, Q2QY53, Q2RAX3, Q2V452, Q38997, Q54DF2, Q54TA3

SIGNOR signaling

8 interactions.

A	Effect	B	Mechanism
STK11	up-regulates	MARK4	phosphorylation
MARK4	“down-regulates activity”	TNK1	phosphorylation
MARK4	“up-regulates activity”	ODF2	phosphorylation
MARK4	“down-regulates activity”	MAPT	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 49 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Centrosome maturation	5	37.3×	1e-05
AURKA Activation by TPX2	6	26.9×	1e-05
Transcriptional and post-translational regulation of MITF-M expression and activity	5	26.2×	4e-05
SARS-CoV-1-host interactions	5	25.8×	4e-05
Apoptosis	5	24.7×	4e-05
Loss of Nlp from mitotic centrosomes	5	23.3×	5e-05
Loss of proteins required for interphase microtubule organization from the centrosome	5	23.3×	5e-05
Translocation of SLC2A4 (GLUT4) to the plasma membrane	5	22.7×	6e-05

GO biological processes:

GO term	Partners	Fold	FDR
intracellular protein localization	5	12.2×	6e-03
protein phosphorylation	7	11.1×	1e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

119 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	90
Likely benign	4
Benign	3

Top pathogenic / likely-pathogenic (0)

SpliceAI

8931 predictions. Top by Δscore:

Variant	Effect	Δscore
19:45090098:A:AG	acceptor_gain	1.0000
19:45090099:C:G	acceptor_gain	1.0000
19:45090102:A:AG	acceptor_gain	1.0000
19:45090105:A:AG	acceptor_gain	1.0000
19:45090105:A:AT	acceptor_loss	1.0000
19:45090106:G:GG	acceptor_gain	1.0000
19:45090106:GC:G	acceptor_gain	1.0000
19:45090106:GCC:G	acceptor_gain	1.0000
19:45090106:GCCA:G	acceptor_gain	1.0000
19:45090106:GCCAA:G	acceptor_gain	1.0000
19:45138512:A:AG	acceptor_gain	1.0000
19:45138513:G:GT	acceptor_gain	1.0000
19:45138513:GCCCA:G	acceptor_gain	1.0000
19:45138610:AGGTA:A	donor_loss	1.0000
19:45138611:GG:G	donor_loss	1.0000
19:45138613:T:G	donor_loss	1.0000
19:45140233:CA:C	acceptor_loss	1.0000
19:45140234:A:AC	acceptor_loss	1.0000
19:45140234:A:AG	acceptor_gain	1.0000
19:45140234:AG:A	acceptor_gain	1.0000
19:45140235:G:GG	acceptor_gain	1.0000
19:45140235:GG:G	acceptor_gain	1.0000
19:45140235:GGA:G	acceptor_gain	1.0000
19:45140235:GGAA:G	acceptor_gain	1.0000
19:45140282:G:GA	donor_loss	1.0000
19:45140504:A:AG	acceptor_gain	1.0000
19:45140504:AG:A	acceptor_gain	1.0000
19:45140504:AGGT:A	acceptor_gain	1.0000
19:45140505:G:GG	acceptor_gain	1.0000
19:45140505:GG:G	acceptor_gain	1.0000

AlphaMissense

4849 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:45259112:T:G	Y59D	1.000
19:45259133:G:A	G66R	1.000
19:45259133:G:C	G66R	1.000
19:45259133:G:T	G66W	1.000
19:45259134:G:A	G66E	1.000
19:45259139:G:A	G68S	1.000
19:45259139:G:C	G68R	1.000
19:45259139:G:T	G68C	1.000
19:45259140:G:A	G68D	1.000
19:45259140:G:C	G68A	1.000
19:45259140:G:T	G68V	1.000
19:45259145:T:A	F70I	1.000
19:45259145:T:C	F70L	1.000
19:45259145:T:G	F70V	1.000
19:45259146:T:C	F70S	1.000
19:45259146:T:G	F70C	1.000
19:45259147:T:A	F70L	1.000
19:45259147:T:G	F70L	1.000
19:45259149:C:A	A71D	1.000
19:45259155:T:A	V73D	1.000
19:45259155:T:C	V73A	1.000
19:45259161:T:C	L75P	1.000
19:45259164:C:A	A76D	1.000
19:45263117:C:A	A86D	1.000
19:45263120:T:A	I87N	1.000
19:45263122:A:C	K88Q	1.000
19:45263122:A:G	K88E	1.000
19:45263124:G:C	K88N	1.000
19:45263124:G:T	K88N	1.000
19:45263129:T:A	I90N	1.000

dbSNP variants (sampled 300 via entrez): RS1000071618 (19:45263840 A>C,G), RS1000146111 (19:45282715 C>T), RS1000172585 (19:45304778 A>C,T), RS1000189526 (19:45259824 C>A,T), RS1000199936 (19:45252010 C>G), RS1000256003 (19:45288197 C>T), RS1000260045 (19:45292993 C>T), RS1000324451 (19:45298846 C>T), RS1000337777 (19:45299733 A>T), RS1000389798 (19:45262863 C>G,T), RS1000398075 (19:45298532 G>T), RS1000425305 (19:45293807 G>T), RS1000509260 (19:45305502 A>C,G,T), RS1000579378 (19:45283102 T>A,G), RS1000605103 (19:45304583 T>C)

Disease associations

OMIM: gene MIM:606495 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
neurodevelopmental disorder	Limited	Autosomal dominant

Mondo (1): neurodevelopmental disorder (MONDO:0700092)

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

59 associations (top):

Study	Trait	p-value
GCST003219_43	Advanced age-related macular degeneration	3.000000e-07
GCST004603_276	Platelet count	3.000000e-30
GCST004603_277	Platelet count	2.000000e-34
GCST004604_42	Hematocrit	8.000000e-09
GCST004606_40	Eosinophil count	1.000000e-15
GCST004607_22	Plateletcrit	9.000000e-27
GCST004609_153	Monocyte percentage of white cells	1.000000e-11
GCST004610_94	White blood cell count	4.000000e-40
GCST004613_75	Sum neutrophil eosinophil counts	5.000000e-35
GCST004614_77	Granulocyte count	1.000000e-34
GCST004616_46	Platelet distribution width	4.000000e-45
GCST004616_47	Platelet distribution width	1.000000e-18
GCST004620_39	Sum basophil neutrophil counts	1.000000e-31
GCST004624_22	Sum eosinophil basophil counts	1.000000e-15
GCST004625_217	Monocyte count	1.000000e-55
GCST004626_160	Myeloid white cell count	3.000000e-41
GCST004629_46	Neutrophil count	4.000000e-32
GCST005950_15	Body mass index x sex x age interaction (4df test)	2.000000e-10
GCST005951_56	Body mass index	1.000000e-06
GCST005952_8	Body mass index (age>50)	9.000000e-12
GCST005954_4	Body mass index x age interaction	2.000000e-07
GCST006701_3	Parental longevity (father’s attained age)	9.000000e-09
GCST007320_16	Alzheimer’s disease or family history of Alzheimer’s disease	2.000000e-38
GCST007320_21	Alzheimer’s disease or family history of Alzheimer’s disease	7.000000e-23
GCST007320_22	Alzheimer’s disease or family history of Alzheimer’s disease	2.000000e-22
GCST007320_41	Alzheimer’s disease or family history of Alzheimer’s disease	5.000000e-13
GCST007320_46	Alzheimer’s disease or family history of Alzheimer’s disease	4.000000e-12
GCST007320_87	Alzheimer’s disease or family history of Alzheimer’s disease	7.000000e-09
GCST007320_89	Alzheimer’s disease or family history of Alzheimer’s disease	1.000000e-08
GCST007827_3	Alzheimer’s disease or HDL levels (pleiotropy)	1.000000e-97

EFO canonical traits (30, from GWAS)

EFO ID	Trait name
EFO:1001492	atrophic macular degeneration
EFO:0004309	platelet count
EFO:0004348	hematocrit
EFO:0004842	eosinophil count
EFO:0007985	platelet crit
EFO:0007989	monocyte percentage of leukocytes
EFO:0004833	neutrophil count
EFO:0007987	granulocyte count
EFO:0007984	platelet component distribution width
EFO:0005090	basophil count
EFO:0005091	monocyte count
EFO:0004340	body mass index
EFO:0008007	age at assessment
EFO:0008343	sex interaction measurement
EFO:0007796	parental longevity
EFO:0009268	family history of Alzheimer’s disease
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0004530	triglyceride measurement
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0004531	urate measurement
EFO:0007701	spine bone mineral density
EFO:0007991	eosinophil percentage of leukocytes
EFO:0004509	hemoglobin measurement
EFO:0007986	reticulocyte count
EFO:0004587	lymphocyte count
EFO:0007993	lymphocyte percentage of leukocytes
EFO:0010701	mean reticulocyte volume
EFO:0007990	neutrophil percentage of leukocytes
EFO:0004305	erythrocyte count
EFO:0009188	Red cell distribution width

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D065886	Neurodevelopmental Disorders	F03.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5754 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

22 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 346,204 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1201092	RIVASTIGMINE TARTRATE	4	13
CHEMBL1287853	FEDRATINIB	4	3,554
CHEMBL502	DONEPEZIL	4	43,493
CHEMBL502835	NINTEDANIB	4	8,545
CHEMBL535	SUNITINIB	4	79,020
CHEMBL608533	MIDOSTAURIN	4	7,259
CHEMBL2105728	CRENOLANIB	3	2,167
CHEMBL39	SEROTONIN	3	186,160
CHEMBL522892	DOVITINIB	3	4,944
CHEMBL603469	LESTAURTINIB	3
CHEMBL1721885	SU-014813	2	363
CHEMBL3115681	NARAZACICLIB	2	287
CHEMBL402548	DANUSERTIB	2	1,928
CHEMBL475251	R-406	2	762
CHEMBL572878	TOZASERTIB	2	2,998
CHEMBL574737	UCN-01	2	2,217
CHEMBL1084546	PF-00562271	1	399
CHEMBL1908397	KW-2449	1	622
CHEMBL2041933	AZD-7762	1	1,240
CHEMBL3128043	PF-03758309	1	233
CHEMBL3544932	TAK-901	1
CHEMBL4289017	PF-03814735	1

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — MARK subfamily

Most potent curated ligand interactions (3 total), top 3:

Ligand	Action	Affinity	Parameter
PCC0208017	Inhibition	8.7	pIC50
PCC0105003	Inhibition	8.57	pIC50
compound 14 [PMID: 34333981]	Inhibition	6.09	pIC50

Binding affinities (BindingDB)

7 measured of 7 human assays (7 total across all organisms); most potent 7 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
Staurosporine	KD	1.7 nM
PKC-412	KD	190 nM
(3Z)-4-amino-5-fluoro-3-[5-(4-methylpiperazino)-1,3-dihydrobenzimidazol-2-ylidene]carbostyril	KD	520 nM
N-[4-({4-[(3-methyl-1H-pyrazol-5-yl)amino]-6-(4-methylpiperazin-1-yl)pyrimidin-2-yl}sulfanyl)phenyl]cyclopropanecarboxamide	KD	1100 nM
5-[(Z)-(5-fluoranyl-2-oxidanylidene-1H-indol-3-ylidene)methyl]-2,4-dimethyl-N-[(2S)-3-morpholin-4-yl-2-oxidanyl-propyl]-1H-pyrrole-3-carboxamide	KD	2600 nM
1-Acyl-1H-[1,2,4]triazole-3,5-diamine Analogue 3b	KD	3100 nM
N-[2-(diethylamino)ethyl]-5-[(Z)-(5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide	KD	3500 nM

ChEMBL bioactivities

115 potent at pChembl≥5 of 128 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.94	IC50	0.114	nM	STAUROSPORINE
9.88	IC50	0.131	nM	STAUROSPORINE
9.87	IC50	0.135	nM	STAUROSPORINE
9.30	Kd	0.5	nM	STAUROSPORINE
9.30	Ki	0.5012	nM	CHEMBL1993661
9.10	Ki	0.7943	nM	CHEMBL1980995
8.70	IC50	2	nM	CHEMBL5305160
8.27	Kd	5.4	nM	STAUROSPORINE
8.22	Kd	6	nM	CHEMBL4465866
8.10	Kd	8	nM	UCN-01
8.10	Ki	7.943	nM	CHEMBL592030
8.05	Kd	9	nM	PF-03814735
7.92	Kd	12	nM	TAE-684
7.68	IC50	21	nM	CHEMBL3884319
7.60	Kd	25	nM	CRENOLANIB
7.55	Kd	28	nM	K-252A
7.54	Kd	29	nM	PF-03758309
7.44	Kd	36	nM	CHEMBL3990456
7.39	IC50	41	nM	CHEMBL3605057
7.30	Ki	50.12	nM	CHEMBL1972346
7.30	Ki	50.12	nM	PF-00562271
7.14	Kd	72	nM	KW-2449
7.14	Kd	73	nM	LESTAURTINIB
7.14	IC50	72	nM	CHEMBL5085430
7.10	Ki	79.43	nM	CHEMBL1998953
7.09	Kd	82.01	nM	CHEMBL3752910
7.05	Kd	89	nM	R-406
7.01	ED50	98.64	nM	CHEMBL3752910
7.00	Ki	100	nM	JNJ-7706621
7.00	Ki	100	nM	R-406
7.00	Ki	100	nM	DOVITINIB
6.92	Kd	120	nM	LESTAURTINIB
6.85	Kd	140	nM	PF-00562271
6.75	IC50	180	nM	CHEMBL3884344
6.68	Kd	210	nM	KW-2449
6.67	IC50	214	nM	CHEMBL5088930
6.63	Kd	232	nM	DANUSERTIB
6.60	Ki	251.2	nM	CHEMBL1974328
6.57	IC50	270	nM	CHEMBL3884318
6.50	IC50	319	nM	CHEMBL3605057
6.47	IC50	338	nM	CHEMBL3916849
6.43	Kd	370	nM	MIDOSTAURIN
6.40	Ki	398.1	nM	CHEMBL458997
6.40	Ki	398.1	nM	CHEMBL1991674
6.35	IC50	450	nM	CHEMBL3883979
6.32	Kd	475	nM	AZD-7762
6.29	IC50	509	nM	CHEMBL5090046
6.28	IC50	520	nM	CHEMBL3883433
6.20	Ki	631	nM	CHEMBL234085
6.18	Kd	660	nM	JNJ-7706621

PubChem BioAssay actives

94 with measured affinity, of 711 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
(2S,3R,4R,6R)-3-methoxy-2-methyl-4-(methylamino)-29-oxa-1,7,17-triazaoctacyclo[12.12.2.12,6.07,28.08,13.015,19.020,27.021,26]nonacosa-8,10,12,14,19,21,23,25,27-nonaen-16-one	1531761: Inhibition of human MARK4 using KKKVSRSGLYRSPSMPENLNRPR as substrate by [gamma-33P]-ATP assay	ic50	0.0001	uM
7-[(1S)-4-hydroxy-2,3-dihydro-1H-inden-1-yl]-5,5-dimethyl-2-[3-(pyrrolidin-1-ylmethyl)anilino]pyrrolo[2,3-d]pyrimidin-6-one	1992917: Inhibition of MARK4 (unknown origin)	ic50	0.0020	uM
3-(2,2-difluoro-10,12-dimethyl-1-aza-3-azonia-2-boranuidatricyclo[7.3.0.03,7]dodeca-3,5,7,9,11-pentaen-4-yl)-N-[2-[2-[2-[2-[[(2S,3R,4R,6R)-3-methoxy-2-methyl-16-oxo-29-oxa-1,7,17-triazaoctacyclo[12.12.2.12,6.07,28.08,13.015,19.020,27.021,26]nonacosa-8,10,12,14,19,21,23,25,27-nonaen-4-yl]amino]ethoxy]ethoxy]ethoxy]ethyl]propanamide	1526131: Binding affinity to recombinant full-length N-terminal His-FLAG-tagged MARK4 (unknown origin) expressed in baculovirus infected Sf9 insect cells incubated for 1 hr by TR-FRET assay	kd	0.0060	uM
(2S,3R,4R,6R,18S)-18-hydroxy-3-methoxy-2-methyl-4-(methylamino)-29-oxa-1,7,17-triazaoctacyclo[12.12.2.12,6.07,28.08,13.015,19.020,27.021,26]nonacosa-8,10,12,14,19,21,23,25,27-nonaen-16-one	1425070: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	0.0080	uM
N-[2-[4-[[4-(cyclobutylamino)-5-(trifluoromethyl)pyrimidin-2-yl]amino]-11-azatricyclo[6.2.1.02,7]undeca-2(7),3,5-trien-11-yl]-2-oxoethyl]acetamide	1425070: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	0.0090	uM
5-chloro-2-N-[2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl]-4-N-(2-propan-2-ylsulfonylphenyl)pyrimidine-2,4-diamine	625140: Binding constant for MARK4 kinase domain	kd	0.0120	uM
2-anilino-7-[(1S)-4-hydroxy-2,3-dihydro-1H-inden-1-yl]-5,5-dimethylpyrrolo[2,3-d]pyrimidin-6-one	1335989: Inhibition of human MARK4 expressed in HEK293T cells coexpressing tau protein assessed as reduction in tau phosphorylation at Ser262 residues by AlphaLisa assay	ic50	0.0210	uM
1-[2-[5-[(3-methyloxetan-3-yl)methoxy]benzimidazol-1-yl]quinolin-8-yl]piperidin-4-amine	1425070: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	0.0250	uM
methyl (15S,16R,18R)-16-hydroxy-15-methyl-3-oxo-28-oxa-4,14,19-triazaoctacyclo[12.11.2.115,18.02,6.07,27.08,13.019,26.020,25]octacosa-1,6,8,10,12,20,22,24,26-nonaene-16-carboxylate	1425070: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	0.0280	uM
N-[(1S)-2-(dimethylamino)-1-phenylethyl]-6,6-dimethyl-3-[(2-methylthieno[3,2-d]pyrimidin-4-yl)amino]-1,4-dihydropyrrolo[3,4-d]pyrazole-5-carboxamide	1425070: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	0.0290	uM
2-amino-2-cyclohexyl-N-[2-(1-methylpyrazol-4-yl)-9-oxo-3,10,11-triazatricyclo[6.4.1.04,13]trideca-1,4,6,8(13),11-pentaen-6-yl]acetamide	1425070: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	0.0360	uM
N-[3-[[5-cyclopropyl-2-[3-(morpholin-4-ylmethyl)anilino]pyrimidin-4-yl]amino]propyl]cyclobutanecarboxamide	1992917: Inhibition of MARK4 (unknown origin)	ic50	0.0410	uM
[4-[(E)-2-(1H-indazol-3-yl)ethenyl]phenyl]-piperazin-1-ylmethanone	1425070: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	0.0720	uM
N-[3-[[5-bromo-4-[3-(cyclobutanecarbonylamino)propylamino]pyrimidin-2-yl]amino]phenyl]pyrrolidine-1-carboxamide	1823774: Displacement of tracer K5 from NLuc fused MARK4 (unknown origin) expressed in HEK293 cells by NanoBRET assay	ic50	0.0720	uM
(15S,16S,18R)-16-hydroxy-16-(hydroxymethyl)-15-methyl-28-oxa-4,14,19-triazaoctacyclo[12.11.2.115,18.02,6.07,27.08,13.019,26.020,25]octacosa-1,6,8,10,12,20,22,24,26-nonaen-3-one	1425070: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	0.0730	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148720: Binding affinity to human MARK4 incubated for 45 mins by Kinobead based pull down assay	kd	0.0820	uM
6-[[5-fluoro-2-(3,4,5-trimethoxyanilino)pyrimidin-4-yl]amino]-2,2-dimethyl-4H-pyrido[3,2-b][1,4]oxazin-3-one	625140: Binding constant for MARK4 kinase domain	kd	0.0890	uM
N-methyl-N-[3-[[[2-[(2-oxo-1,3-dihydroindol-5-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]methyl]-2-pyridinyl]methanesulfonamide	1425070: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	0.1400	uM
N-[(1S)-1-(2-anilino-5,5-dimethyl-6-oxopyrrolo[2,3-d]pyrimidin-7-yl)-2,3-dihydro-1H-inden-4-yl]methanesulfonamide	1335989: Inhibition of human MARK4 expressed in HEK293T cells coexpressing tau protein assessed as reduction in tau phosphorylation at Ser262 residues by AlphaLisa assay	ic50	0.1800	uM
5-bromo-4-N-[2-(1H-imidazol-5-yl)ethyl]-2-N-[3-(morpholin-4-ylmethyl)phenyl]pyrimidine-2,4-diamine	1823774: Displacement of tracer K5 from NLuc fused MARK4 (unknown origin) expressed in HEK293 cells by NanoBRET assay	ic50	0.2140	uM
N-[5-[(2R)-2-methoxy-2-phenylacetyl]-4,6-dihydro-1H-pyrrolo[3,4-d]pyrazol-3-yl]-4-(4-methylpiperazin-1-yl)benzamide	1425070: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	0.2320	uM
7-[(1S)-1-(3-hydroxyphenyl)ethyl]-5,5-dimethyl-2-(pyridin-3-ylamino)pyrrolo[2,3-d]pyrimidin-6-one	1335989: Inhibition of human MARK4 expressed in HEK293T cells coexpressing tau protein assessed as reduction in tau phosphorylation at Ser262 residues by AlphaLisa assay	ic50	0.2700	uM
N-[3-[[5-bromo-4-[2-(1H-imidazol-5-yl)ethylamino]pyrimidin-2-yl]amino]phenyl]pyrrolidine-1-carboxamide	1823774: Displacement of tracer K5 from NLuc fused MARK4 (unknown origin) expressed in HEK293 cells by NanoBRET assay	ic50	0.3380	uM
Midostaurin	435924: Binding constant for MARK4 kinase domain	kd	0.3700	uM
7-[(1S)-4-amino-2,3-dihydro-1H-inden-1-yl]-2-anilino-5,5-dimethylpyrrolo[2,3-d]pyrimidin-6-one	1335989: Inhibition of human MARK4 expressed in HEK293T cells coexpressing tau protein assessed as reduction in tau phosphorylation at Ser262 residues by AlphaLisa assay	ic50	0.4500	uM
3-(carbamoylamino)-5-(3-fluorophenyl)-N-[(3S)-piperidin-3-yl]thiophene-2-carboxamide	1425070: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	0.4750	uM
N-[3-[[4-[3-(cyclobutanecarbonylamino)propylamino]-5-cyclopropylpyrimidin-2-yl]amino]phenyl]pyrrolidine-1-carboxamide	1823774: Displacement of tracer K5 from NLuc fused MARK4 (unknown origin) expressed in HEK293 cells by NanoBRET assay	ic50	0.5090	uM
7-[(1S)-2,3-dihydro-1H-inden-1-yl]-5,5-dimethyl-2-(pyridin-3-ylamino)pyrrolo[2,3-d]pyrimidin-6-one	1335989: Inhibition of human MARK4 expressed in HEK293T cells coexpressing tau protein assessed as reduction in tau phosphorylation at Ser262 residues by AlphaLisa assay	ic50	0.5200	uM
4-[[5-amino-1-(2,6-difluorobenzoyl)-1,2,4-triazol-3-yl]amino]benzenesulfonamide	435924: Binding constant for MARK4 kinase domain	kd	0.6600	uM
5-cyclopropyl-4-N-[2-(1H-imidazol-5-yl)ethyl]-2-N-[3-(morpholin-4-ylmethyl)phenyl]pyrimidine-2,4-diamine	1823774: Displacement of tracer K5 from NLuc fused MARK4 (unknown origin) expressed in HEK293 cells by NanoBRET assay	ic50	0.8080	uM
7-cyclohexyl-5,5-dimethyl-2-(3-piperazin-1-ylanilino)pyrrolo[2,3-d]pyrimidin-6-one	1335989: Inhibition of human MARK4 expressed in HEK293T cells coexpressing tau protein assessed as reduction in tau phosphorylation at Ser262 residues by AlphaLisa assay	ic50	0.9200	uM
Fedratinib	625140: Binding constant for MARK4 kinase domain	kd	0.9700	uM
4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-quinolin-2-one	1425070: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	0.9760	uM
5-(3-ethylsulfonylphenyl)-3,8-dimethyl-N-(1-methylpiperidin-4-yl)-9H-pyrido[2,3-b]indole-7-carboxamide	1425070: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	1.0350	uM
N-[(2-hydroxy-7-methyl-1H-indol-3-yl)imino]-1-[(4-methoxyphenyl)methyl]triazole-4-carboxamide	1613202: Inhibition of human recombinant MARK4 expressed in Escherichia coli M15 cells after 2 hrs in presence of [gamma-32-P]ATP by TLC analysis based ATPase assay	ic50	1.5400	uM
[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]-(5-oxo-10H-phenothiazin-2-yl)methanone	2100321: Inhibition of human MARK4 expressed in Escherichia coli preincubated for 1 hr followed by ATP addition and measured after 30 mins by colorimetric assay	ic50	1.7400	uM
1,3,6-trihydroxy-7-methoxy-2,8-bis(3-methylbut-2-enyl)xanthen-9-one	1539198: Inhibition of recombinant human MARK4 incubated for 2 hrs by [gamma32P]ATP assay	ic50	1.7700	uM
N-benzyl-2-(2-methyl-9-oxoacridin-10-yl)acetamide	1978492: Inhibition of human MARK4 ATPase activity using ATP as substrate incubated for 10 to 20 mins by Biomol green reagent based ELISA analysis	ic50	1.8000	uM
2-(2-methyl-9-oxoacridin-10-yl)-N-(4-methylphenyl)acetamide	1978492: Inhibition of human MARK4 ATPase activity using ATP as substrate incubated for 10 to 20 mins by Biomol green reagent based ELISA analysis	ic50	1.8000	uM
N-[(4-methoxyphenyl)methyl]-2-(2-methyl-9-oxoacridin-10-yl)acetamide	1978492: Inhibition of human MARK4 ATPase activity using ATP as substrate incubated for 10 to 20 mins by Biomol green reagent based ELISA analysis	ic50	1.8000	uM
(10-methylphenothiazin-2-yl)-(2-phenylimidazo[1,2-a]pyridin-3-yl)methanone	2100321: Inhibition of human MARK4 expressed in Escherichia coli preincubated for 1 hr followed by ATP addition and measured after 30 mins by colorimetric assay	ic50	1.8800	uM
6,8-dichloro-2-(furan-2-yl)-3-(4-iodoanilino)chromen-4-one	1422449: Inhibition of MARK4 (unknown origin) (59 to 368 residues) expressed in Escherichia coli M15 in presence of [gamma-32P]ATP by ATPase assay	ic50	1.9800	uM
5-[(Z)-(5-fluoro-2-oxo-1H-indol-3-ylidene)methyl]-N-[(2S)-2-hydroxy-3-morpholin-4-ylpropyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide	435924: Binding constant for MARK4 kinase domain	kd	2.0000	uM
methyl 2-hydroxy-3-[N-[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]phenyl]-C-phenylcarbonimidoyl]-1H-indole-6-carboxylate	625140: Binding constant for MARK4 kinase domain	kd	2.0000	uM
6,8-dichloro-2-(furan-2-yl)-3-(4-nitroanilino)chromen-4-one	1422449: Inhibition of MARK4 (unknown origin) (59 to 368 residues) expressed in Escherichia coli M15 in presence of [gamma-32P]ATP by ATPase assay	ic50	2.1200	uM
[3-(4-nitrophenyl)imidazo[1,2-a]pyridin-2-yl]-(10H-phenothiazin-2-yl)methanone	2100321: Inhibition of human MARK4 expressed in Escherichia coli preincubated for 1 hr followed by ATP addition and measured after 30 mins by colorimetric assay	ic50	2.1600	uM
[2-(4-nitrophenyl)imidazo[1,2-a]pyridin-3-yl]-(10H-phenothiazin-2-yl)methanone	2100321: Inhibition of human MARK4 expressed in Escherichia coli preincubated for 1 hr followed by ATP addition and measured after 30 mins by colorimetric assay	ic50	2.2400	uM
(10-butylphenothiazin-2-yl)-(2-phenylimidazo[1,2-a]pyridin-3-yl)methanone	2100321: Inhibition of human MARK4 expressed in Escherichia coli preincubated for 1 hr followed by ATP addition and measured after 30 mins by colorimetric assay	ic50	2.7200	uM
5,5-dimethyl-7-[(1S)-1-phenylethyl]-2-(pyridin-3-ylamino)pyrrolo[2,3-d]pyrimidin-6-one	1335989: Inhibition of human MARK4 expressed in HEK293T cells coexpressing tau protein assessed as reduction in tau phosphorylation at Ser262 residues by AlphaLisa assay	ic50	2.7500	uM
[3-(4-bromophenyl)imidazo[1,2-a]pyridin-2-yl]-(10-butylphenothiazin-2-yl)methanone	2100321: Inhibition of human MARK4 expressed in Escherichia coli preincubated for 1 hr followed by ATP addition and measured after 30 mins by colorimetric assay	ic50	2.7700	uM

CTD chemical–gene interactions

37 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases methylation	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Valproic Acid	affects expression, increases expression	2
Cadmium Chloride	decreases expression, increases abundance, increases expression	2
GSK-J4	increases expression	1
dicrotophos	increases expression	1
triphenyl phosphate	affects expression	1
propylparaben	increases expression	1
titanium dioxide	decreases methylation	1
cinnamaldehyde	decreases expression	1
afimoxifene	decreases response to substance	1
cypermethrin	decreases expression	1
sodium arsenite	increases expression	1
vanillin	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	decreases expression, affects cotreatment	1
ON 01910	increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
Resveratrol	decreases expression, affects cotreatment	1
Fulvestrant	increases methylation	1
Leflunomide	increases expression	1
Acetaminophen	increases expression	1
Cadmium	decreases expression, increases abundance	1
Caffeine	decreases phosphorylation	1
Doxorubicin	increases expression	1
Endosulfan	increases expression	1
Lead	affects splicing	1
Plant Extracts	decreases expression, affects cotreatment	1
Smoke	decreases expression	1
Tetrachlorodibenzodioxin	affects expression	1
Thimerosal	decreases expression	1

ChEMBL screening assays

246 unique, capped per target: 245 binding, 1 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1047442	Binding	Inhibition of MARK4 assessed as enzyme activity at 1 uM relative to untreated control	Selective inhibitors of the mutant B-Raf pathway: discovery of a potent and orally bioavailable aminoisoquinoline. — J Med Chem
CHEMBL1963713	Functional	PUBCHEM_BIOASSAY: Navigating the Kinome. (Class of assay: other) Panel member name: MARK4	PubChem BioAssay data set

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_SX18	HAP1 MARK4 (-) 1	Cancer cell line	Male
CVCL_SX19	HAP1 MARK4 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

202 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT01783041	PHASE2/PHASE3	COMPLETED	Effect of Early L-Carnitine Supplementation on Neurodevelopmental Outcomes in Very Preterm Infants
NCT05767385	PHASE2/PHASE3	RECRUITING	Fetal Cerebrovascular Autoregulation in Congenital Heart Disease and Association With Neonatal Neurobehavior
NCT05675098	EARLY_PHASE1	NOT_YET_RECRUITING	Central Nervous System Stimulants and Physical Function in Children With Cerebral Palsy
NCT00783783	Not specified	COMPLETED	CYP2D6 Pharmacogenetics in Risperidone-Treated Children
NCT01778504	Not specified	RECRUITING	Studying Childhood-onset Behavioral, Psychiatric, and Developmental Disorders
NCT01850784	Not specified	UNKNOWN	High Energy Formula Feeding in Infants With Congenital Heart Disease
NCT01922791	Not specified	COMPLETED	Nutrition and Pregnancy Intervention Study
NCT01942525	Not specified	UNKNOWN	Influence of Intrauterine Growth Restriction on Amplitude-integrated EEG in Preterm Infants
NCT02003170	Not specified	COMPLETED	Etiology and Early Diagnosis of Neurodevelopmental Disorders
NCT02118649	Not specified	ACTIVE_NOT_RECRUITING	Enhancing Behavior and Brain Response to Visual Targets Using a Computer Game
NCT02557191	Not specified	TERMINATED	Biomarkers, Neurodevelopment and Preterm Infants
NCT02690675	Not specified	COMPLETED	Iron Supplement Effect on Child Development
NCT02694003	Not specified	COMPLETED	Better Nights, Better Days for Children With Neurodevelopment Disorders
NCT02792894	Not specified	COMPLETED	Family Networks (FaNs) for Children With Developmental Disorders and Delays
NCT02871674	Not specified	UNKNOWN	Good Night Project: Behavioural Sleep Interventions for Children With ADHD: A Randomised Controlled Trial
NCT02887157	Not specified	COMPLETED	Analyzing Retinal Microanatomy in ROP
NCT02898298	Not specified	COMPLETED	Positive Emotion Regulation Training in Children, Adolescents and Young Adults With and Without Developmental Disorder
NCT02912780	Not specified	UNKNOWN	Introduction of Microsystems in a Level 3 Neonatal Intensive Care Unit
NCT03023293	Not specified	COMPLETED	n-3 PUFAs, Irisin and Maternal Glucose Metabolism From Pregnancy to Postpartum
NCT03023644	Not specified	COMPLETED	Improving Neurodevelopmental Outcomes in Children With Congenital Heart Disease: An Intervention Study
NCT03032991	Not specified	UNKNOWN	Early Biomarkers of Neurodevelopment in Offspring of Diabetic Mothers
NCT03088189	Not specified	TERMINATED	Effect of Parental Peri-conceptional Vitamin B12 Supplementation on Infant Neurocognitive Development in Offspring
NCT03096028	Not specified	COMPLETED	Developmental Origins of Mental Health Disorders
NCT03148782	Not specified	COMPLETED	Brain Plasticity Underlying Acquisition of New Organizational Skills in Children-R61 Phase
NCT03172104	Not specified	COMPLETED	Neurobehavioural Development of Infants Born <30 Weeks Gestational Age Between Birth and Five Years of Age
NCT03222375	Not specified	RECRUITING	SQUED™ Series 28.1 Home-use and Treatment of Autowave Reverberator of Autism
NCT03229928	Not specified	COMPLETED	Clinical Testing of a Real-Time Behavior Measurement Tool: Measuring Outcomes for CHAnge
NCT03232489	Not specified	UNKNOWN	Study for the Evaluation of the Feasibility of Applying Advanced MRI Scanning in Pediatric Clinical Practice