MARK1

Summary

MARK1 (microtubule affinity regulating kinase 1, HGNC:6896) is a protein-coding gene on chromosome 1q41, encoding Serine/threonine-protein kinase MARK1 (Q9P0L2). Serine/threonine-protein kinase.

Enables several functions, including ATP binding activity; magnesium ion binding activity; and phospholipid binding activity. Involved in intracellular signal transduction; negative regulation of epithelial to mesenchymal transition; and protein phosphorylation. Located in cytoplasm; dendrite; and plasma membrane.

Source: NCBI Gene 4139 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 101 total
• Druggable target: yes — 15 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_018650

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6896
Approved symbol	MARK1
Name	microtubule affinity regulating kinase 1
Location	1q41
Locus type	gene with protein product
Status	Approved
Aliases	MARK, PAR-1C
Ensembl gene	ENSG00000116141
Ensembl biotype	protein_coding
OMIM	606511
Entrez	4139

Gene structure

Transcript identifiers

Ensembl transcripts: 31 — 19 protein_coding, 9 retained_intron, 2 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000366917, ENST00000366918, ENST00000402574, ENST00000485104, ENST00000611084, ENST00000676500, ENST00000677041, ENST00000677074, ENST00000677173, ENST00000677505, ENST00000677551, ENST00000678353, ENST00000678409, ENST00000678435, ENST00000678473, ENST00000678857, ENST00000678922, ENST00000679033, ENST00000853993, ENST00000853994, ENST00000853995, ENST00000853996, ENST00000915633, ENST00000915634, ENST00000915635, ENST00000946911, ENST00000946912, ENST00000946913, ENST00000946914, ENST00000946915, ENST00000946916

RefSeq mRNA: 5 — MANE Select: NM_018650 NM_001286124, NM_001286126, NM_001286128, NM_001286129, NM_018650

CCDS: CCDS31029, CCDS65789, CCDS73033, CCDS73034

Canonical transcript exons

ENST00000366917 — 18 exons

Exon	Start	End
ENSE00001068912	220635376	220635529
ENSE00001068915	220653101	220653352
ENSE00001068916	220650620	220650720
ENSE00001068917	220635833	220636026
ENSE00001068918	220615939	220615995
ENSE00001068920	220657790	220657834
ENSE00001068921	220632201	220632313
ENSE00001068923	220651986	220652150
ENSE00001068924	220631035	220631134
ENSE00001068926	220618636	220618755
ENSE00001837704	220528136	220528873
ENSE00002255055	220618310	220618546
ENSE00002289956	220604067	220604137
ENSE00003719508	220581065	220581118
ENSE00003727379	220579354	220579557
ENSE00003737483	220598331	220598379
ENSE00003751055	220599798	220599863
ENSE00003899501	220661812	220664461

Expression profiles

Bgee: expression breadth ubiquitous, 257 present calls, max score 95.09.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 11.2614 / max 357.7497, expressed in 1002 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
8640	9.9720	979
8642	0.7379	344
8643	0.3020	169
8644	0.1440	63
8641	0.1055	35

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cortical plate	UBERON:0005343	95.09	gold quality
ganglionic eminence	UBERON:0004023	93.87	gold quality
ventricular zone	UBERON:0003053	93.18	gold quality
corpus epididymis	UBERON:0004359	88.62	gold quality
embryo	UBERON:0000922	86.70	gold quality
pons	UBERON:0000988	86.62	gold quality
cerebellar vermis	UBERON:0004720	85.98	gold quality
Brodmann (1909) area 23	UBERON:0013554	85.35	gold quality
superior frontal gyrus	UBERON:0002661	85.26	gold quality
dorsal root ganglion	UBERON:0000044	85.24	gold quality
endothelial cell	CL:0000115	85.08	gold quality
primary visual cortex	UBERON:0002436	85.04	gold quality
prefrontal cortex	UBERON:0000451	84.89	gold quality
parietal lobe	UBERON:0001872	84.69	gold quality
postcentral gyrus	UBERON:0002581	84.66	gold quality
occipital lobe	UBERON:0002021	84.47	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	84.35	gold quality
superior vestibular nucleus	UBERON:0007227	84.26	gold quality
neocortex	UBERON:0001950	84.01	gold quality
popliteal artery	UBERON:0002250	83.95	gold quality
tibial artery	UBERON:0007610	83.94	gold quality
islet of Langerhans	UBERON:0000006	83.79	gold quality
frontal cortex	UBERON:0001870	83.76	gold quality
Brodmann (1909) area 9	UBERON:0013540	83.44	gold quality
cerebral cortex	UBERON:0000956	83.32	gold quality
lateral nuclear group of thalamus	UBERON:0002736	83.30	gold quality
sperm	CL:0000019	83.23	gold quality
Brodmann (1909) area 46	UBERON:0006483	83.09	gold quality
anterior cingulate cortex	UBERON:0009835	83.07	gold quality
cingulate cortex	UBERON:0003027	83.03	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-GEOD-75367	no	119.86
E-ANND-3	no	5.33

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

3 targets.

Target	Regulation
CDH1	Activation
CDH2	Repression
VIM	Repression

Upstream regulators (CollecTRI, top): EZH2, KDM5A, SP7, TP53

miRNA regulators (miRDB)

195 targeting MARK1, 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-5692A	100.00	74.40	6850
HSA-MIR-4262	100.00	73.26	3931
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-27A-3P	99.98	72.13	2955

Literature-anchored findings (GeneRIF, showing 10)

• analysis of variations in the catalytic and ubiquitin-associated domains of microtubule-associated protein/microtubule affinity regulating kinase (MARK) 1 and MARK2 (PMID:16803889)
• MARK1 was overexpressed in a prefrontal region in the brains of patients with Autism spectrum disorders. (PMID:18492799)
• Data show that protein kinases of the MARK family phosphorylate tau protein in its repeat domain and thereby regulate its affinity for microtubules and affect the aggregation of tau into Alzheimer paired helical filaments. (PMID:19090997)
• In the Australian GWAS, the SNP rs7530302 near MARK1 on chromosome 1 (p=1.90 x 10(-9) achieved genomewide significance for comorbid AD/ND. (PMID:20158304)
• the positioning of MARK/Par-1 at the crosstalk of regulating cytoskeletal dynamics allows its participation in neuronal polarity decisions. [review] (PMID:24243102)
• LKB1 acts through its substrates of the microtubule affinity-regulating kinase family to regulate the localization of the polarity determinant Scribble and the activity of the core Hippo kinases (PMID:24362629)
• Molecular determinants of KA1 domain-mediated autoinhibition and phospholipid activation of MARK1 kinase have been described. (PMID:27879374)
• Low MARK1 is associated with cervical cancer. (PMID:29076440)
• Structural basis for MARK1 kinase autoinhibition by its KA1 domain has been uncovered. (PMID:30099988)
• Microtubule affinity regulating kinase 1 (MARK1) is a direct target of miR-23a in colorectal cancer (CRC) cells. (PMID:31281935)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio		ENSDARG00000113295
mus_musculus	Mark1	ENSMUSG00000026620
rattus_norvegicus	Mark1	ENSRNOG00000002339

Paralogs (3): MARK4 (ENSG00000007047), MARK2 (ENSG00000072518), MARK3 (ENSG00000075413)

Protein

Protein identifiers

Serine/threonine-protein kinase MARK1 — Q9P0L2 (reviewed: Q9P0L2)

Alternative names: MAP/microtubule affinity-regulating kinase 1, PAR1 homolog c

All UniProt accessions (8): Q9P0L2, A0A087X0I6, A0A7I2V4P8, A0A7I2V550, A0A7I2V624, A0A7I2YQC1, B4DIB3, X5D2M4

UniProt curated annotations — full annotation on UniProt →

Function. Serine/threonine-protein kinase. Involved in cell polarity and microtubule dynamics regulation. Phosphorylates DCX, MAP2 and MAP4. Phosphorylates the microtubule-associated protein MAPT/TAU. Involved in cell polarity by phosphorylating the microtubule-associated proteins MAP2, MAP4 and MAPT/TAU at KXGS motifs, causing detachment from microtubules, and their disassembly. Involved in the regulation of neuronal migration through its dual activities in regulating cellular polarity and microtubule dynamics, possibly by phosphorylating and regulating DCX. Also acts as a positive regulator of the Wnt signaling pathway, probably by mediating phosphorylation of dishevelled proteins (DVL1, DVL2 and/or DVL3).

Subunit / interactions. Interacts with MAPT/TAU.

Subcellular location. Cell membrane. Cytoplasm. Cytoskeleton. Cell projection. Dendrite.

Tissue specificity. Highly expressed in heart, skeletal muscle, brain, fetal brain and fetal kidney.

Post-translational modifications. Phosphorylation at Thr-613 by PRKCZ/aPKC in polarized epithelial cells inhibits the kinase activity. Phosphorylated at Thr-215 by STK11/LKB1 in complex with STE20-related adapter-alpha (STRADA) pseudo kinase and CAB39. Phosphorylation at Thr-215 by TAOK1 activates the kinase activity, leading to phosphorylation and detachment of MAPT/TAU from microtubules. Phosphorylation at Ser-219 by GSK3-beta (GSK3B) inhibits the kinase activity.

Disease relevance. Genetic variations in MARK1 may be associated with susceptibility to autism. MARK1 is overexpressed in the prefrontal cortex of patients with autism and causes changes in the function of cortical dendrites.

Activity regulation. Inhibited by phosphorylation at Ser-219. Activated by phosphorylation on Thr-215.

Domain organisation. The UBA domain does not seem to bind ubiquitin and ubiquitin-like and might play a role in regulating the enzyme conformation and localization. Activation of the kinase activity following phosphorylation at Thr-208 is accompanied by a conformational change that alters the orientation of the UBA domain with respect to the catalytic domain. The KA1 domain mediates binding to phospholipids and targeting to membranes. Binds phosphatidic acid (PA), phosphatidylserine (PtdSer) and phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2).

Miscellaneous. Phosphorylation of MAPT/tau by MARK1 could play a role in early steps of Alzheimer disease. Pathological aggregation of MAPT/tau to neurofibrillary tangles, filamentous structures consisting of paired helical filaments (PHFs), is one of the hallmarks of Alzheimer disease. Hyperphosphorylation by MARK1 could be the initial step for this abnormal aggregation of tau in Alzheimer disease and animal models of tauopathy.

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

Isoforms (3)

UniProt ID	Names	Canonical?
Q9P0L2-1	1	yes
Q9P0L2-2	2
Q9P0L2-3	3

RefSeq proteins (4): NP_001273053, NP_001273055, NP_001273057, NP_061120* (*=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), 4 shown:

• L-seryl-[tau protein] + ATP = O-phospho-L-seryl-[tau protein] + ADP + H(+) (RHEA:12801)
• 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)
• L-threonyl-[tau protein] + ATP = O-phospho-L-threonyl-[tau protein] + ADP + H(+) (RHEA:53904)

UniProt features (89 total): helix 19, modified residue 14, strand 13, compositionally biased region 9, sequence variant 6, sequence conflict 6, mutagenesis site 5, turn 4, domain 3, splice variant 3, region of interest 3, binding site 2, chain 1, active site 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
3OSE	X-RAY DIFFRACTION	1.7
6C9D	X-RAY DIFFRACTION	2.5
2HAK	X-RAY DIFFRACTION	2.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9P0L2-F1	68.33	0.42

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): 182 (proton acceptor)

Ligand- & substrate-binding residues (2): 66–74; 89

Post-translational modifications (14): 5, 208, 215, 219, 382, 390, 393, 403, 423, 444, 475, 588, 613, 666

Mutagenesis-validated functional residues (5):

Position	Phenotype
215	prevents phosphorylation and activation by stk11/lkb1 complex.
215	constitutively active.
698	impairs phospholipid-binding, targeting to membrane and vesicle-binding; when associated with s-701.
701	impairs phospholipid-binding, targeting to membrane and vesicle-binding; when associated with s-698.
771–773	impairs phospholipid-binding.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 272 (showing top): GOBP_DENDRITE_DEVELOPMENT, AP1_01, GOBP_SYNAPSE_ASSEMBLY, GAUSSMANN_MLL_AF4_FUSION_TARGETS_A_UP, GOBP_NEUROGENESIS, GOBP_REGULATION_OF_CELL_JUNCTION_ASSEMBLY, TAL1ALPHAE47_01, GOBP_NEGATIVE_REGULATION_OF_EPITHELIAL_TO_MESENCHYMAL_TRANSITION, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, GTACAGG_MIR486, ACEVEDO_LIVER_CANCER_WITH_H3K27ME3_UP, GOBP_NEGATIVE_REGULATION_OF_MULTICELLULAR_ORGANISMAL_PROCESS, GOBP_REGULATION_OF_CELL_PROJECTION_ORGANIZATION, GOBP_CELL_JUNCTION_ORGANIZATION, AP1_Q4_01

GO Biological Process (13): microtubule cytoskeleton organization (GO:0000226), neuron migration (GO:0001764), protein phosphorylation (GO:0006468), cytoskeleton organization (GO:0007010), positive regulation of gene expression (GO:0010628), negative regulation of gene expression (GO:0010629), negative regulation of epithelial to mesenchymal transition (GO:0010719), regulation of neuron projection development (GO:0010975), Wnt signaling pathway (GO:0016055), intracellular signal transduction (GO:0035556), regulation of dendrite development (GO:0050773), establishment of mitochondrion localization (GO:0051654), regulation of postsynapse assembly (GO:0150052)

GO Molecular Function (16): magnesium ion binding (GO:0000287), phosphatidylserine binding (GO:0001786), protein serine/threonine kinase activity (GO:0004674), ATP binding (GO:0005524), phosphatidylinositol-4,5-bisphosphate binding (GO:0005546), tau protein binding (GO:0048156), tau-protein kinase activity (GO:0050321), phosphatidic acid binding (GO:0070300), protein serine kinase activity (GO:0106310), nucleotide binding (GO:0000166), protein kinase activity (GO:0004672), protein binding (GO:0005515), lipid binding (GO:0008289), kinase activity (GO:0016301), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (9): cytoplasm (GO:0005737), cytoskeleton (GO:0005856), plasma membrane (GO:0005886), microtubule cytoskeleton (GO:0015630), dendrite (GO:0030425), postsynapse (GO:0098794), glutamatergic synapse (GO:0098978), membrane (GO:0016020), cell projection (GO:0042995)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
gene expression	2
regulation of gene expression	2
intracellular anatomical structure	2
phospholipid binding	2
anion binding	2
protein kinase activity	2
binding	2
synapse	2
cytoskeleton organization	1
microtubule-based process	1
cell migration	1
generation of neurons	1
phosphorylation	1
protein modification process	1
organelle organization	1
positive regulation of macromolecule biosynthetic process	1
negative regulation of macromolecule biosynthetic process	1
epithelial to mesenchymal transition	1
regulation of epithelial to mesenchymal transition	1
negative regulation of cell differentiation	1
negative regulation of multicellular organismal process	1
neuron projection development	1
regulation of plasma membrane bounded cell projection organization	1
cell surface receptor signaling pathway	1
signal transduction	1
regulation of neuron projection development	1
dendrite development	1
regulation of developmental process	1
mitochondrion localization	1
establishment of organelle localization	1
regulation of synapse assembly	1
postsynapse assembly	1
regulation of postsynapse organization	1
metal ion binding	1
modified amino acid binding	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
phosphatidylinositol phosphate binding	1
phosphatidylinositol bisphosphate binding	1

Protein interactions and networks

STRING

604 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MARK1	ZC3H14	Q6PJT7	639
MARK1	HOOK2	Q96ED9	587
MARK1	MAPT	P10636	531
MARK1	YWHAQ	P27348	507
MARK1	LRP8	Q14114	493
MARK1	PUSL1	Q8N0Z8	493
MARK1	SIK2	Q9H0K1	483
MARK1	MAD2L1	Q13257	477
MARK1	GRIK4	Q16099	471
MARK1	MAD1L1	Q9Y6D9	470
MARK1	MYC	P01106	465
MARK1	FSD1	Q9BTV5	464
MARK1	TP53	P04637	456
MARK1	DAPK1	P53355	455
MARK1	SIK3	Q9Y2K2	449

IntAct

87 interactions, top by confidence:

A	B	Type	Score
	TOMM70	psi-mi:“MI:0914”(association)	0.690
YWHAH	PLEKHG3	psi-mi:“MI:0914”(association)	0.610
YWHAB	BLTP3B	psi-mi:“MI:0914”(association)	0.610
Cdc20	BUB1	psi-mi:“MI:0914”(association)	0.560
MARK1	DYNLT1	psi-mi:“MI:0915”(physical association)	0.560
DYNLT1	MARK1	psi-mi:“MI:0915”(physical association)	0.560
TCL1B	MARK1	psi-mi:“MI:0915”(physical association)	0.560
INCA1	MARK1	psi-mi:“MI:0915”(physical association)	0.560
YAF2	MARK1	psi-mi:“MI:0915”(physical association)	0.560
APP	MARK1	psi-mi:“MI:0915”(physical association)	0.560
MARK1	YWHAE	psi-mi:“MI:0914”(association)	0.530
YWHAQ	IGLC7	psi-mi:“MI:0914”(association)	0.530
	NHERF1	psi-mi:“MI:0914”(association)	0.530
YWHAZ	BLTP3B	psi-mi:“MI:0914”(association)	0.530
EPS8L1	DHPS	psi-mi:“MI:0914”(association)	0.530
NCK1	SH3PXD2B	psi-mi:“MI:0914”(association)	0.530
PNMA2	CCDC85C	psi-mi:“MI:0914”(association)	0.530
NRAS	ESYT2	psi-mi:“MI:2364”(proximity)	0.480
YWHAB	PLEKHG3	psi-mi:“MI:0914”(association)	0.480
YWHAQ	PLEKHG3	psi-mi:“MI:0914”(association)	0.480
MARK1	MAPT	psi-mi:“MI:2364”(proximity)	0.480
MARK1	SF3A2	psi-mi:“MI:0915”(physical association)	0.400
MARK1	SFN	psi-mi:“MI:0915”(physical association)	0.400
MARK1	GJA5	psi-mi:“MI:0915”(physical association)	0.370
	AURKA	psi-mi:“MI:0914”(association)	0.350
MARK1	LATS1	psi-mi:“MI:0914”(association)	0.350

BioGRID (117): MARK1 (Affinity Capture-MS), MARK1 (Affinity Capture-MS), MARK1 (Affinity Capture-MS), MARK1 (Affinity Capture-MS), MARK1 (Reconstituted Complex), MARK1 (Affinity Capture-RNA), MARK1 (Affinity Capture-MS), MARK1 (Proximity Label-MS), MARK1 (Affinity Capture-MS), MAPT (Biochemical Activity), MAPT (Biochemical Activity), MARK1 (Affinity Capture-MS), MARK1 (Biochemical Activity), MARK1 (Affinity Capture-Western), LRRK2 (Affinity Capture-Western)

ESM2 similar proteins: A1CFB3, A1CHL6, A1CWW9, A1CX69, A1CYS1, A2QNQ5, A2QQ79, A7ERM5, A7EWF5, A7F0W2, A7KAK6, A7KAL2, A7KAN4, B0Y6I4, B6QIB3, B8MKT9, C4B4E5, G4N525, I1RNG8, I1S8Q3, J4W0G2, O08678, P0CP52, P78621, Q0CKU4, Q0CLX3, Q0UY53, Q1DN93, Q1DS65, Q2H6X2, Q2U0C3, Q2UGZ7, Q3ZDQ4, Q4WHB7, Q4WID6, Q4WKP8, Q4WPF2, Q4WPP2, Q4WWM8, Q52EB3

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

18 interactions.

A	Effect	B	Mechanism
STK11	up-regulates	MARK1	phosphorylation
MARK1	down-regulates	MAPT	phosphorylation
MARK1	“down-regulates activity”	TNK1	phosphorylation
MARK1	“down-regulates activity”	MAP2	phosphorylation
MARK1	“down-regulates activity”	MAP4	phosphorylation
MARK1	“down-regulates activity”	MAPT	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 79 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
Activation of BAD and translocation to mitochondria	7	100.5×	5e-11
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	7	88.7×	7e-11
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	7	88.7×	7e-11
Activation of BH3-only proteins	7	65.6×	6e-10
RHO GTPases activate PKNs	7	41.9×	2e-08
Intrinsic Pathway for Apoptosis	7	38.7×	3e-08
RAF activation	5	31.7×	8e-06
FOXO-mediated transcription	5	31.7×	8e-06

GO biological processes:

GO term	Partners	Fold	FDR
protein targeting	5	25.4×	3e-04
intracellular protein localization	8	11.6×	3e-04
protein phosphorylation	9	8.5×	3e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	74
Likely benign	6
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

4064 predictions. Top by Δscore:

Variant	Effect	Δscore
1:220528870:AAAT:A	donor_gain	1.0000
1:220528871:AAT:A	donor_gain	1.0000
1:220528872:AT:A	donor_gain	1.0000
1:220528872:ATG:A	donor_loss	1.0000
1:220528874:G:GG	donor_gain	1.0000
1:220551095:T:TA	acceptor_gain	1.0000
1:220551103:A:AG	acceptor_gain	1.0000
1:220551103:AAGAT:A	acceptor_gain	1.0000
1:220551104:A:G	acceptor_gain	1.0000
1:220551104:AGATG:A	acceptor_gain	1.0000
1:220551105:GATGG:G	acceptor_gain	1.0000
1:220551241:C:G	donor_gain	1.0000
1:220551249:AGC:A	donor_gain	1.0000
1:220551250:GC:G	donor_gain	1.0000
1:220551250:GCG:G	donor_gain	1.0000
1:220551252:G:GG	donor_gain	1.0000
1:220579351:TA:T	acceptor_loss	1.0000
1:220579352:A:AG	acceptor_gain	1.0000
1:220579352:AGC:A	acceptor_loss	1.0000
1:220579353:G:GT	acceptor_gain	1.0000
1:220579353:GC:G	acceptor_gain	1.0000
1:220579353:GCA:G	acceptor_gain	1.0000
1:220579353:GCAT:G	acceptor_gain	1.0000
1:220579353:GCATA:G	acceptor_gain	1.0000
1:220579553:GAGAG:G	donor_gain	1.0000
1:220579555:GAG:G	donor_gain	1.0000
1:220579556:AGG:A	donor_loss	1.0000
1:220579557:GGT:G	donor_loss	1.0000
1:220579558:G:GG	donor_gain	1.0000
1:220579558:G:T	donor_loss	1.0000

AlphaMissense

5225 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:220579480:T:G	Y60D	1.000
1:220579501:G:A	G67R	1.000
1:220579501:G:C	G67R	1.000
1:220579501:G:T	G67W	1.000
1:220579502:G:A	G67E	1.000
1:220579502:G:T	G67V	1.000
1:220579507:G:A	G69R	1.000
1:220579507:G:C	G69R	1.000
1:220579508:G:A	G69E	1.000
1:220579508:G:C	G69A	1.000
1:220579508:G:T	G69V	1.000
1:220579512:T:A	N70K	1.000
1:220579512:T:G	N70K	1.000
1:220579513:T:A	F71I	1.000
1:220579513:T:C	F71L	1.000
1:220579513:T:G	F71V	1.000
1:220579514:T:C	F71S	1.000
1:220579514:T:G	F71C	1.000
1:220579515:T:A	F71L	1.000
1:220579515:T:G	F71L	1.000
1:220579516:G:C	A72P	1.000
1:220579517:C:A	A72D	1.000
1:220579517:C:T	A72V	1.000
1:220579523:T:A	V74D	1.000
1:220579523:T:C	V74A	1.000
1:220579532:C:A	A77E	1.000
1:220581069:C:A	A87D	1.000
1:220581074:A:G	K89E	1.000
1:220581076:A:C	K89N	1.000
1:220581076:A:T	K89N	1.000

dbSNP variants (sampled 300 via entrez): RS1000069738 (1:220583065 C>G,T), RS1000105131 (1:220572100 A>G), RS1000149033 (1:220544580 G>A), RS1000163236 (1:220658669 G>A,T), RS1000169340 (1:220631375 A>G), RS1000182019 (1:220544905 A>T), RS1000198301 (1:220595443 C>T), RS1000214831 (1:220531034 C>T), RS1000234287 (1:220624054 T>C), RS1000248132 (1:220578669 G>C), RS1000259416 (1:220551271 G>A), RS1000286695 (1:220646394 C>G,T), RS1000290987 (1:220620223 A>T), RS1000317677 (1:220639420 A>G), RS1000338707 (1:220646003 C>CAA)

Disease associations

OMIM: gene MIM:606511 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST001343_9	Fat distribution (HIV)	7.000000e-06
GCST001359_2	Bipolar disorder	6.000000e-08
GCST003985_21	Breast size	8.000000e-07

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004341	body fat distribution

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5940 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

15 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 123,640 (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
CHEMBL1287853	FEDRATINIB	4	3,554
CHEMBL3545311	BRIGATINIB	4	5,634
CHEMBL502835	NINTEDANIB	4	8,545
CHEMBL535	SUNITINIB	4	79,020
CHEMBL608533	MIDOSTAURIN	4	7,259
CHEMBL3137331	DEFACTINIB	3	1,229
CHEMBL522892	DOVITINIB	3	4,944
CHEMBL603469	LESTAURTINIB	3
CHEMBL1721885	SU-014813	2	363
CHEMBL3115681	NARAZACICLIB	2	287
CHEMBL4116008	CERDULATINIB	2	2,083
CHEMBL475251	R-406	2	762
CHEMBL572878	TOZASERTIB	2	2,998
CHEMBL607707	PELITINIB	2	6,340
CHEMBL1908397	KW-2449	1	622

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 (2 total), top 2:

Ligand	Action	Affinity	Parameter
PCC0105003	Inhibition	8.52	pIC50
7-hydroxystaurosporine	Inhibition	7.57	pIC50

Binding affinities (BindingDB)

8 measured of 9 human assays (9 total across all organisms); most potent 8 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
(E)-N-[4-(3-chloro-4-fluoro-anilino)-3-cyano-7-ethoxy-6-quinolyl]-4-(dimethylamino)but-2-enamide	KD	3500 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

49 potent at pChembl≥5 of 52 total, top 40 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.58	IC50	0.261	nM	STAUROSPORINE
9.48	IC50	0.328	nM	STAUROSPORINE
9.38	IC50	0.417	nM	STAUROSPORINE
8.70	IC50	2	nM	CHEMBL5305160
8.52	Kd	3	nM	CHEMBL4576489
8.40	IC50	4	nM	CERDULATINIB
8.40	Kd	4	nM	STAUROSPORINE
8.05	Kd	9	nM	CHEMBL4465866
7.57	IC50	27	nM	CHEMBL3605057
7.51	Kd	31	nM	TAE-684
7.08	Kd	83	nM	LESTAURTINIB
6.96	IC50	110	nM	CHEMBL1940251
6.94	IC50	115	nM	CHEMBL2064628
6.90	IC50	127	nM	BRIGATINIB
6.77	Kd	170	nM	MIDOSTAURIN
6.68	Kd	207	nM	CHEMBL408019
6.57	Kd	270	nM	R-406
6.51	Kd	310	nM	KW-2449
6.35	IC50	448	nM	DEFACTINIB
6.23	IC50	590	nM	CHEMBL1940252
6.21	Kd	620	nM	JNJ-7706621
6.16	Kd	700	nM	FEDRATINIB
6.00	IC50	1000	nM	TP-030-1
6.00	IC50	1000	nM	TP-030-2
6.00	IC50	1000	nM	TP-030n
5.92	Kd	1200	nM	SUNITINIB
5.89	IC50	1300	nM	CHEMBL1940253
5.85	Kd	1400	nM	NINTEDANIB
5.83	IC50	1490	nM	CHEMBL2312654
5.82	Kd	1500	nM	SU-014813
5.80	IC50	1585	nM	CHEMBL6167301
5.64	Kd	2300	nM	DOVITINIB
5.50	IC50	3162	nM	CHEMBL190684
5.50	IC50	3162	nM	CHEMBL6170125
5.40	Kd	4000	nM	PELITINIB
5.38	Kd	4200	nM	CHEMBL1908395
5.31	Kd	4900	nM	TOZASERTIB
5.31	Kd	4900	nM	CGP-52421
5.20	IC50	6310	nM	NARAZACICLIB
5.10	IC50	7943	nM	CHEMBL6177408

PubChem BioAssay actives

41 with measured affinity, of 824 total; 29 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	1715286: Inhibition of human MARK1 using KKKVSRSGLYRSPSMPENLNRPR as substrate by [gamma-33P]-ATP assay	ic50	0.0003	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	1992915: Inhibition of MARK1 (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]-methylamino]ethoxy]ethoxy]ethoxy]ethyl]propanamide	1526316: Binding affinity to recombinant full-length N-terminal His-FLAG-tagged MARK1 (unknown origin) expressed in baculovirus infected Sf9 insect cells incubated for 1 hr by TR-FRET assay	kd	0.0030	uM
4-(cyclopropylamino)-2-[4-(4-ethylsulfonylpiperazin-1-yl)anilino]pyrimidine-5-carboxamide	1993896: Inhibition of MARK1 (unknown origin)	ic50	0.0040	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	1526316: Binding affinity to recombinant full-length N-terminal His-FLAG-tagged MARK1 (unknown origin) expressed in baculovirus infected Sf9 insect cells incubated for 1 hr by TR-FRET assay	kd	0.0090	uM
N-[3-[[5-cyclopropyl-2-[3-(morpholin-4-ylmethyl)anilino]pyrimidin-4-yl]amino]propyl]cyclobutanecarboxamide	1992915: Inhibition of MARK1 (unknown origin)	ic50	0.0270	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	625113: Binding constant for MARK1 kinase domain	kd	0.0310	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	507607: Binding affinity to MARK1	kd	0.0830	uM
(2R,3R)-3-[[6-(4-amino-7-propan-2-ylpyrrolo[2,3-d]pyrimidine-5-carbonyl)pyrazin-2-yl]amino]-2-(4-fluorophenyl)pyrrolidine-1-carbaldehyde	642041: Inhibition of MARK1	ic50	0.1100	uM
[(1S)-2-(dimethylamino)-1-phenylethyl] 3-(2,2-dimethylpropanoylamino)-6,6-dimethyl-1,4-dihydropyrrolo[3,4-d]pyrazole-5-carboxylate	676060: Inhibition of MARK1	ic50	0.1150	uM
Brigatinib	2182834: Inhibition of human MARK1 using KKKVSRSGLYRSPSMPENLNRPR as substrate in presence of [gamma33P]-ATP by HotSpot assay	ic50	0.1270	uM
Midostaurin	435807: Binding constant for MARK1 kinase domain	kd	0.1700	uM
N-[6-(3-hydroxyphenyl)-1H-pyrazolo[5,4-b]pyridin-3-yl]cyclopropanecarboxamide	389081: Binding affinity to human MARK1	kd	0.2070	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	625113: Binding constant for MARK1 kinase domain	kd	0.2700	uM
[4-[(E)-2-(1H-indazol-3-yl)ethenyl]phenyl]-piperazin-1-ylmethanone	625113: Binding constant for MARK1 kinase domain	kd	0.3100	uM
1-[(2R,3R)-3-[[6-(4-amino-7-propan-2-ylpyrrolo[2,3-d]pyrimidine-5-carbonyl)pyrazin-2-yl]amino]-2-(4-fluorophenyl)pyrrolidin-1-yl]ethanone	642041: Inhibition of MARK1	ic50	0.5900	uM
4-[[5-amino-1-(2,6-difluorobenzoyl)-1,2,4-triazol-3-yl]amino]benzenesulfonamide	435807: Binding constant for MARK1 kinase domain	kd	0.6200	uM
Fedratinib	625113: Binding constant for MARK1 kinase domain	kd	0.7000	uM
Momelotinib	2183906: Inhibition of MARK1 (unknown origin)	ic50	1.0000	uM
Sunitinib	435807: Binding constant for MARK1 kinase domain	kd	1.2000	uM
1-[(2R,3R)-3-[[6-(4-amino-7-propan-2-ylpyrrolo[2,3-d]pyrimidine-5-carbonyl)pyrazin-2-yl]amino]-2-phenylpyrrolidin-1-yl]ethanone	642041: Inhibition of MARK1	ic50	1.3000	uM
methyl 2-hydroxy-3-[N-[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]phenyl]-C-phenylcarbonimidoyl]-1H-indole-6-carboxylate	625113: Binding constant for MARK1 kinase domain	kd	1.4000	uM
2-N-(3,5-dichlorophenyl)-4-N-[4-(dimethylamino)cyclohexyl]-5-(3-methyl-1,2-oxazol-5-yl)pyrimidine-2,4-diamine	720969: Inhibition of MARK1 (unknown origin) in presence of ATP	ic50	1.4900	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	435807: Binding constant for MARK1 kinase domain	kd	1.5000	uM
4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-quinolin-2-one	435807: Binding constant for MARK1 kinase domain	kd	2.3000	uM
(E)-N-[4-(3-chloro-4-fluoroanilino)-3-cyano-7-ethoxyquinolin-6-yl]-4-(dimethylamino)but-2-enamide	435807: Binding constant for MARK1 kinase domain	kd	4.0000	uM
5-cyano-N-[2-(cyclohexen-1-yl)-4-[1-[2-(dimethylamino)acetyl]piperidin-4-yl]phenyl]-1H-imidazole-2-carboxamide;hydrochloride	625113: Binding constant for MARK1 kinase domain	kd	4.2000	uM
N-[(2S,3R,4R,6R,18S)-18-hydroxy-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]-N-methylbenzamide	507607: Binding affinity to MARK1	kd	4.9000	uM
N-[4-[4-(4-methylpiperazin-1-yl)-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]sulfanylphenyl]cyclopropanecarboxamide	435807: Binding constant for MARK1 kinase domain	kd	4.9000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression, decreases methylation, increases expression	4
sodium arsenite	increases abundance, increases expression	3
bisphenol A	decreases expression, increases methylation	2
trichostatin A	affects expression, decreases reaction, increases expression	2
Nickel	affects expression, decreases expression, decreases reaction	2
FR900359	affects phosphorylation	1
methylmercuric chloride	decreases expression	1
beta-lapachone	increases expression	1
arsenite	decreases expression	1
potassium chromate(VI)	increases expression	1
oxophenylarsine	decreases reaction, increases activity, increases phosphorylation	1
S-(1,2-dichlorovinyl)cysteine	decreases reaction, increases expression	1
CGP 52608	affects binding, increases reaction	1
entinostat	decreases expression	1
abrine	increases expression	1
jinfukang	affects cotreatment, decreases expression	1
Decitabine	increases expression	1
Sunitinib	increases expression	1
Arsenic	increases abundance, increases expression	1
Atrazine	decreases expression	1
Cisplatin	affects cotreatment, decreases expression	1
Dibutyl Phthalate	affects cotreatment, decreases expression	1
Doxorubicin	decreases expression	1
Lipopolysaccharides	increases expression, decreases reaction	1
Tetradecanoylphorbol Acetate	affects cotreatment, decreases expression	1
Tobacco Smoke Pollution	increases expression	1
Vanadates	decreases expression	1
Cyclosporine	increases expression	1
Antirheumatic Agents	increases expression	1
Staurosporine	decreases reaction, increases activity	1

ChEMBL screening assays

326 unique, capped per target: 326 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1012702	Binding	Inhibition of MARK1 at 5 uM	Synthesis and evaluation of novel inhibitors of Pim-1 and Pim-2 protein kinases. — J Med Chem

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_SX10	HAP1 MARK1 (-) 1	Cancer cell line	Male
CVCL_SX11	HAP1 MARK1 (-) 2	Cancer cell line	Male
CVCL_SX12	HAP1 MARK1 (-) 3	Cancer cell line	Male

Clinical trials (associated diseases)

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