MARCKS

Summary

MARCKS (myristoylated alanine rich protein kinase C substrate, HGNC:6759) is a protein-coding gene on chromosome 6q21, encoding Myristoylated alanine-rich C-kinase substrate (P29966). Membrane-associated protein that plays a role in the structural modulation of the actin cytoskeleton, chemotaxis, motility, cell adhesion, phagocytosis, and exocytosis through lipid sequestering and/or protein docking to membranes.

The protein encoded by this gene is a substrate for protein kinase C. It is localized to the plasma membrane and is an actin filament crosslinking protein. Phosphorylation by protein kinase C or binding to calcium-calmodulin inhibits its association with actin and with the plasma membrane, leading to its presence in the cytoplasm. The protein is thought to be involved in cell motility, phagocytosis, membrane trafficking and mitogenesis.

Source: NCBI Gene 4082 — RefSeq curated summary.

At a glance

• GWAS associations: 6
• Clinical variants (ClinVar): 102 total — 1 likely-pathogenic
• Druggable target: yes
• MANE Select transcript: NM_002356

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6759
Approved symbol	MARCKS
Name	myristoylated alanine rich protein kinase C substrate
Location	6q21
Locus type	gene with protein product
Status	Approved
Aliases	PKCSL, 80K-L
Ensembl gene	ENSG00000277443
Ensembl biotype	protein_coding
OMIM	177061
Entrez	4082

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000612661, ENST00000932583

RefSeq mRNA: 1 — MANE Select: NM_002356 NM_002356

CCDS: CCDS5101

Canonical transcript exons

ENST00000612661 — 2 exons

Exon	Start	End
ENSE00003719216	113857345	113857847
ENSE00003727485	113859683	113863475

Expression profiles

Bgee: expression breadth ubiquitous, 294 present calls, max score 99.58.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 502.7854 / max 6241.5276, expressed in 1693 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
69362	472.9847	1681
69364	14.9041	1487
69363	9.1410	1420
69380	5.5026	1265
204165	0.2530	122

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ventricular zone	UBERON:0003053	99.58	gold quality
ganglionic eminence	UBERON:0004023	99.57	gold quality
buccal mucosa cell	CL:0002336	99.46	gold quality
embryo	UBERON:0000922	99.45	gold quality
cortical plate	UBERON:0005343	99.22	gold quality
colonic mucosa	UBERON:0000317	99.20	gold quality
mucosa of sigmoid colon	UBERON:0004993	99.20	gold quality
medial globus pallidus	UBERON:0002477	99.15	gold quality
bronchial epithelial cell	CL:0002328	98.95	gold quality
trigeminal ganglion	UBERON:0001675	98.95	gold quality
mucosa of paranasal sinus	UBERON:0005030	98.88	gold quality
globus pallidus	UBERON:0001875	98.84	gold quality
superior vestibular nucleus	UBERON:0007227	98.82	gold quality
mammary duct	UBERON:0001765	98.79	gold quality
dorsal root ganglion	UBERON:0000044	98.67	gold quality
ventral tegmental area	UBERON:0002691	98.57	gold quality
inferior vagus X ganglion	UBERON:0005363	98.53	gold quality
superficial temporal artery	UBERON:0001614	98.51	gold quality
subthalamic nucleus	UBERON:0001906	98.49	gold quality
adult organism	UBERON:0007023	98.42	gold quality
cerebellar vermis	UBERON:0004720	98.37	gold quality
olfactory bulb	UBERON:0002264	98.36	gold quality
periodontal ligament	UBERON:0008266	98.36	gold quality
cartilage tissue	UBERON:0002418	98.34	gold quality
epithelium of mammary gland	UBERON:0003244	98.30	gold quality
calcaneal tendon	UBERON:0003701	98.21	gold quality
pylorus	UBERON:0001166	98.19	gold quality
paraflocculus	UBERON:0005351	98.11	gold quality
mammalian vulva	UBERON:0000997	98.10	gold quality
oral cavity	UBERON:0000167	98.07	gold quality

Single-cell (SCXA)

Detected in 32 experiment(s), a significant marker in 27.

Experiment	Marker?	Max mean expression
E-GEOD-98556	yes	6723.53
E-HCAD-24	yes	1676.52
E-GEOD-149689	yes	1321.73
E-MTAB-8271	yes	999.96
E-MTAB-8060	yes	781.77
E-CURD-95	yes	129.87
E-MTAB-10287	yes	108.34
E-MTAB-6701	yes	74.32
E-MTAB-8142	yes	46.21
E-MTAB-6678	yes	45.09
E-MTAB-9467	yes	39.63
E-MTAB-9221	yes	35.78
E-HCAD-10	yes	35.19
E-HCAD-11	yes	31.74
E-HCAD-4	yes	25.30

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CUX1

miRNA regulators (miRDB)

174 targeting MARCKS, 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-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-3925-3P	100.00	69.95	1237
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-499A-5P	99.98	70.79	1323
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-34C-5P	99.97	70.45	1577
HSA-MIR-449B-5P	99.97	70.26	1580
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-3912-5P	99.95	66.11	925

Literature-anchored findings (GeneRIF, showing 40)

• Myristoylated alanine-rich C kinase substrate (MARCKS) sequesters spin-labeled phosphatidylinositol 4,5-bisphosphate in lipid bilayers. (PMID:11825894)
• role in interaction with calmodulin (PMID:14506265)
• MARCKS proteolysis is necessary for the fusion of myoblasts. (PMID:15239673)
• MARCKS-mediated neurotensin release occurs via protein kinase C-delta downstream of the Rho/ROK pathwaymediated neurotensin release occurs via protein kinase C-delta downstream of the Rho/ROK pathway (PMID:15623535)
• elevations in MARCKS expression are detrimental to specific aspects of hippocampal function (PMID:15889447)
• These findings suggest that some PDBu-induced MARCKS phosphorylation includes the RhoA/ROCK pathway in SH-SY5Y cells. (PMID:16677610)
• Results suggest that unphosphorylated MARCKS is involved in neurite initiation, and highlight the important role played by MARCKS in organization of the actin cytoskeleton. (PMID:16941482)
• We suggest that the downregulation of MRP by beta3 is not required for increased cell spreading but instead that MRP downregulation is a secondary effect of increased cell spreading. (PMID:17292354)
• PKC delta plays an important role in mucin secretion by airway epithelium via regulation of MARCKS phosphorylation. (PMID:18055557)
• First evidence that cysteine string protein and HSP70, and their interactions with MARCKS, are involved in mucin secretion from airway epithelium. (PMID:18314541)
• The present study indicates that MARCKS play a major key role in PDGF-BB-induced chemotaxis in activated human hepatic stellate cells. (PMID:18329017)
• identify MARCKS as a pathogenic contributor to intimal hyperplasia (PMID:18940893)
• These data suggested that miR-21 could promote apoptosis resistance, motility, and invasion in prostate cancer cells and these effects of miR-21 may be partly due to its regulation of PDCD4, TPM1, and MARCKS. (PMID:19302977)
• MARCKS regulates lamellipodia formation induced by IGF-I via association with PIP2 and beta-actin at membrane microdomains. (PMID:19475567)
• MARCKS, via its myristoylated aminoterminus, is a key regulator of neutrophil migration and adhesion. (PMID:19574534)
• Myristoylated alanine-rich protein kinase C substrate (MARCKS), previously implicated in cell adhesion and motility, contributes to EGFR-mediated invasion of human GBM cells. (PMID:19773446)
• reducing MRP expression promotes formation of adherens junctions in EpRas cells, allowing collective cell migration, but interferes with oncogenic beta-catenin signaling and tumorigenesis (PMID:19924305)
• role for MARCKS as one of the key players in the migration of CCA cells and suggest that cycling between MARCKS and pMARCKS can regulate the metastasis of biliary cancer cells. (PMID:20047593)
• MARCKS and related chaperones bind to unconventional myosin V isoforms in airway epithelial cells (PMID:20203291)
• BK promotes neurite outgrowth through transient MARCKS phosphorylation involving the PKC-dependent RhoA/ROCK pathway and PP2A in a neuroblastoma cell line. (PMID:21448919)
• Relative mRNA expression of MARCKS in white blood cells of O. viverrini-infected patients was higher than in healthy subjects; thus, MARCKS is expressed in macrophages and plays a role in inflammation-related cholangiocarcinoma induced by O. viverrini. (PMID:21763456)
• These findings implicate that MARCKS is essential for proper cytokinesis and that MARCKS and its partner actin are key mitotic regulators during cell cycle in human hepatic stellate cells. (PMID:22555845)
• Cleavage ofMARCKS by Calpain may have an important role in regulation of the PKC/MARCKS pathway regulating airway mucin secretion (PMID:22710197)
• a critical role for H(2)O(2) in angiotensin-II signaling to the endothelial cytoskeleton in a novel pathway that is critically dependent on MARCKS, Rac1, and c-Abl. (PMID:22773836)
• MARCKS plays an articulated role in the progression of colorectal cancer (PMID:23376641)
• heat shock protein 70 (HSP70) and cysteine string protein (CSP), associate with MARCKS in the secretory mechanism in bronchial epithelial cells (PMID:23377348)
• MARCKS is a negative modulator of the acrosomal exocytosis. (PMID:23704996)
• High MARCKS expression is associated with therapeutic responsiveness in breast cancer. (PMID:23876235)
• MARCKS may represent a potential biomarker for the prognosis of primary lung SCC. (PMID:24240590)
• decreased MARCKS and pMARCKS in the frontal cortex in schizophrenia was found; results suggest a mechanism other than myristoylation was responsible for decreased MARCKS expression in schizophrenia (PMID:24568864)
• Finding that MARCKS acts as a mediator of apoptosis in microsatellite stable colorectal cancer cells adds a novel tumor-suppressing function to the established roles of MARCKS in cell motility and proliferation. (PMID:24662837)
• Phospho-MARCKS, a post-translational modification, is associated with cell motility, and has a role in the regulation of cancer cell invasiveness and metastasis. (PMID:24735036)
• MARCKS overexpression was observed in several drug-resistant human myeloma cell lines and in drug-resistant primary multiple myeloma samples. (PMID:25179733)
• results suggest a key role for MARCKS PSD in cancer disease and provide a unique strategy for inhibiting the activity of MARCKS PSD as a treatment for lung cancer. (PMID:25318062)
• isotype delta-PKC is responsible for myristoylated alanine-rich C-kinase substrate (MARCKS) phosphorylation in human neutrophils following f-Met-Leu-Phe stimulation and MARCKS phosphorylation is essential for neutrophil migration and adhesion. (PMID:25515270)
• A key role of the effector domain of MARCKS in terms of cellular response, particularly to radiation: the importance of MARCKS phosphorylation status for its subcellular localization in lung cancer. (PMID:25524703)
• MARCKS and PPP1R9A might contribute to spine loss in schizophrenia and bipolar disorder through their interactions. (PMID:25757715)
• unresponsiveness of breast cancer to paclitaxel treatment is, at least in part, mediated by phospho-MARCKS (PMID:26015406)
• MARCKS upregulation increases vascular smooth muscle cell motility by activation of Rac1 and Cdc42, promoting neointima formation. (PMID:26450120)
• A novel role for MARCKS in regulating nuclear functions such as gene expression. (PMID:26470026)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	marcksa	ENSDARG00000004049
mus_musculus	Marcks	ENSMUSG00000069662
rattus_norvegicus	Marcks	ENSRNOG00000000579

Paralogs (1): MARCKSL1 (ENSG00000175130)

Protein

Protein identifiers

Myristoylated alanine-rich C-kinase substrate — P29966 (reviewed: P29966)

Alternative names: Protein kinase C substrate, 80 kDa protein, light chain

All UniProt accessions (1): P29966

UniProt curated annotations — full annotation on UniProt →

Function. Membrane-associated protein that plays a role in the structural modulation of the actin cytoskeleton, chemotaxis, motility, cell adhesion, phagocytosis, and exocytosis through lipid sequestering and/or protein docking to membranes. Thus, exerts an influence on a plethora of physiological processes, such as embryonic development, tissue regeneration, neuronal plasticity, and inflammation. Sequesters phosphatidylinositol 4,5-bisphosphate (PIP2) at lipid rafts in the plasma membrane of quiescent cells, an action reversed by protein kinase C, ultimately inhibiting exocytosis. During inflammation, promotes the migration and adhesion of inflammatory cells and the secretion of cytokines such as tumor necrosis factor (TNF), particularly in macrophages. Plays an essential role in bacteria-induced intracellular reactive oxygen species (ROS) formation in the monocytic cell type. Participates in the regulation of neurite initiation and outgrowth by interacting with components of cellular machinery including CDC42 that regulates cell shape and process extension through modulation of the cytoskeleton. Plays also a role in axon development by mediating docking and fusion of RAB10-positive vesicles with the plasma membrane.

Subunit / interactions. Interacts with CDC42. Interacts with GTP-bound form of RAB10. Interacts with calmodulin/CALM1.

Subcellular location. Cell membrane. Cytoplasm. Cytoskeleton.

Tissue specificity. Detected in spermatozoa.

Post-translational modifications. Phosphorylation by PKC displaces MARCKS from the membrane. It also inhibits the F-actin cross-linking activity. PKC-mediated phosphorylation increases 4 to 5-fold upon TNF or LPS induction. Myristoylated. A proper myristoylation is essential for the proper distribution to the plasma membrane. Acetylated at Lys-172 by KAT5; acetylation is required for its subsequent phosphorylation. Deacetylated by SIRT2.

Induction. By TNF and LPS in monocytes.

Similarity. Belongs to the MARCKS family.

RefSeq proteins (1): NP_002347* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002101	MARCKS	Family

Pfam: PF02063

UniProt features (42 total): modified residue 22, compositionally biased region 7, sequence conflict 6, region of interest 2, sequence variant 2, initiator methionine 1, chain 1, lipid moiety-binding region 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
1IWQ	X-RAY DIFFRACTION	2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P29966-F1	50.42	0.00

Functional residue map

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

Post-translational modifications (23): 26, 27, 29, 46, 63, 77, 81, 101, 118, 128, 135, 143, 145, 147, 150, 159, 163, 167, 170, 172 …

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-399997	Acetylcholine regulates insulin secretion
R-HSA-1430728	Metabolism
R-HSA-163685	Integration of energy metabolism
R-HSA-422356	Regulation of insulin secretion

MSigDB gene sets: 490 (showing top): LI_CISPLATIN_RESISTANCE_DN, DAVIES_MULTIPLE_MYELOMA_VS_MGUS_DN, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, FREAC2_01, GOBP_ACTIN_FILAMENT_BUNDLE_ORGANIZATION, PAL_PRMT5_TARGETS_UP, GOBP_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS, GOZGIT_ESR1_TARGETS_DN, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, DITTMER_PTHLH_TARGETS_UP, HSIAO_HOUSEKEEPING_GENES, JOHANSSON_GLIOMAGENESIS_BY_PDGFB_UP, GOBP_NEUROGENESIS, GOBP_NEURAL_TUBE_DEVELOPMENT

GO Biological Process (9): apoptotic process (GO:0006915), mitochondrion organization (GO:0007005), actin filament organization (GO:0007015), central nervous system development (GO:0007417), neural tube development (GO:0021915), neurogenesis (GO:0022008), response to endoplasmic reticulum stress (GO:0034976), actin filament bundle assembly (GO:0051017), actin crosslink formation (GO:0051764)

GO Molecular Function (5): protein kinase C binding (GO:0005080), calmodulin binding (GO:0005516), identical protein binding (GO:0042802), actin filament binding (GO:0051015), actin binding (GO:0003779)

GO Cellular Component (18): nucleoplasm (GO:0005654), cytoplasm (GO:0005737), endoplasmic reticulum (GO:0005783), centrosome (GO:0005813), cytosol (GO:0005829), plasma membrane (GO:0005886), focal adhesion (GO:0005925), cilium (GO:0005929), cell cortex (GO:0005938), actin cytoskeleton (GO:0015629), nuclear speck (GO:0016607), cell junction (GO:0030054), actin filament bundle (GO:0032432), germinal vesicle (GO:0042585), extracellular exosome (GO:0070062), cytoskeleton (GO:0005856), membrane (GO:0016020), organelle (GO:0043226)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Regulation of insulin secretion	1
Metabolism	1
Integration of energy metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	7
nervous system development	3
cytoplasm	3
protein binding	2
cell periphery	2
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
organelle organization	1
actin cytoskeleton organization	1
supramolecular fiber organization	1
system development	1
tube development	1
chordate embryonic development	1
epithelium development	1
cell differentiation	1
cellular response to stress	1
cellular component assembly	1
actin filament bundle organization	1
actin filament organization	1
protein kinase binding	1
actin binding	1
protein-containing complex binding	1
cytoskeletal protein binding	1
nuclear lumen	1
intracellular anatomical structure	1
endomembrane system	1
intracellular membrane-bounded organelle	1
centriole	1
microtubule organizing center	1
membrane	1
cell-substrate junction	1
intraciliary transport particle	1
membrane-bounded organelle	1
plasma membrane bounded cell projection	1
cytoskeleton	1
nuclear ribonucleoprotein granule	1
actin filament	1
actin cytoskeleton	1
female germ cell nucleus	1

Protein interactions and networks

STRING

2024 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MARCKS	CALM1	P02593	995
MARCKS	CALML6	Q8TD86	995
MARCKS	CALML3	P27482	995
MARCKS	CALML5	Q9NZT1	995
MARCKS	CALML4	Q96GE6	995
MARCKS	BASP1	P80723	919
MARCKS	DGKZ	Q13574	845
MARCKS	SYN1	P17600	835
MARCKS	SYN3	O14994	814
MARCKS	SYN2	Q92777	809
MARCKS	ADD2	P35612	779
MARCKS	PRKCSH	P14314	764
MARCKS	DGKI	O75912	755
MARCKS	ADD3	Q9UEY8	745
MARCKS	ADD1	P35611	744

IntAct

78 interactions, top by confidence:

A	B	Type	Score
	TOMM70	psi-mi:“MI:0914”(association)	0.980
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
CFTR	PLEKHG3	psi-mi:“MI:0914”(association)	0.480
NRAS	ESYT2	psi-mi:“MI:2364”(proximity)	0.480
	MYL12B	psi-mi:“MI:0914”(association)	0.460
TXN2	MARCKS	psi-mi:“MI:0915”(physical association)	0.370
		psi-mi:“MI:0914”(association)	0.350
	VWA8	psi-mi:“MI:0914”(association)	0.350
	IPO5	psi-mi:“MI:0914”(association)	0.350
	ESYT2	psi-mi:“MI:0914”(association)	0.350
	PGRMC1	psi-mi:“MI:0914”(association)	0.350
PHOSPHO1	DDX39A	psi-mi:“MI:0914”(association)	0.350
PLEKHA7	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
MAPT	MEX3A	psi-mi:“MI:0914”(association)	0.350
MAPT	POTEF	psi-mi:“MI:0914”(association)	0.350
ESR1	ESYT2	psi-mi:“MI:0914”(association)	0.350
MAPK13	DDX3X	psi-mi:“MI:0914”(association)	0.350

BioGRID (689): MARCKS (Affinity Capture-MS), MARCKS (Affinity Capture-MS), MARCKS (Affinity Capture-MS), MARCKS (Proximity Label-MS), MARCKS (Affinity Capture-MS), MARCKS (Affinity Capture-MS), MARCKS (Reconstituted Complex), MARCKS (Proximity Label-MS), MARCKS (Affinity Capture-MS), MARCKS (Affinity Capture-MS), MARCKS (Affinity Capture-MS), MARCKS (Affinity Capture-MS), MARCKS (Affinity Capture-MS), MARCKS (Affinity Capture-MS), MARCKS (Affinity Capture-MS)

ESM2 similar proteins: A2QUR1, A2WMG6, B0WQG0, O42932, O77788, P05114, P06180, P06302, P12036, P12274, P12902, P15308, P16527, P23614, P26645, P27864, P29746, P29966, P30009, P34618, P50887, P54938, P80723, P80724, P91027, Q02508, Q05175, Q0JPA6, Q10020, Q17Q32, Q1RM09, Q23794, Q3ZBV4, Q54LY8, Q56WH4, Q56WK6, Q56ZI2, Q5R715, Q5ZIR5, Q6PD99

Diamond homologs: P12624, P16527, P26645, P29966, P30009, P49006, P28667, P35566, Q0VBZ9, Q6PD99, Q9EPH2, Q6NWH2

SIGNOR signaling

24 interactions.

A	Effect	B	Mechanism
PRKCA	unknown	MARCKS	phosphorylation
PRKCA	“down-regulates activity”	MARCKS	phosphorylation
PKN1	“down-regulates activity”	MARCKS	phosphorylation
PRKCB	unknown	MARCKS	phosphorylation
PRKCD	unknown	MARCKS	phosphorylation
PKN1	unknown	MARCKS	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 83 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
Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants	5	49.0×	7e-06
Downstream signal transduction	5	35.9×	2e-05
Signaling by FGFR1 in disease	5	27.6×	5e-05
Signaling by SCF-KIT	5	23.4×	8e-05
Signaling by BRAF and RAF1 fusions	5	16.1×	3e-04
VEGFA-VEGFR2 Pathway	6	15.8×	8e-05
PIP3 activates AKT signaling	7	8.8×	3e-04
Signaling by Receptor Tyrosine Kinases	7	6.8×	9e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	1
Uncertain significance	84
Likely benign	4
Benign	3

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
521555	NM_002356.7(MARCKS):c.616_632del (p.Glu206fs)	Likely pathogenic

SpliceAI

347 predictions. Top by Δscore:

Variant	Effect	Δscore
6:113859678:CTTA:C	acceptor_loss	1.0000
6:113859679:TTA:T	acceptor_loss	1.0000
6:113859681:A:AG	acceptor_gain	1.0000
6:113859681:AG:A	acceptor_gain	1.0000
6:113859681:AGG:A	acceptor_loss	1.0000
6:113859682:G:A	acceptor_loss	1.0000
6:113859682:G:GT	acceptor_gain	1.0000
6:113859682:GG:G	acceptor_gain	1.0000
6:113859682:GGA:G	acceptor_gain	1.0000
6:113859682:GGAGA:G	acceptor_gain	1.0000
6:113857843:GACAG:G	donor_gain	0.9900
6:113859673:T:TA	acceptor_gain	0.9900
6:113857848:G:GG	donor_gain	0.9700
6:113859119:TGCCA:T	donor_gain	0.9400
6:113857384:G:GT	donor_gain	0.9000
6:113858884:C:T	donor_gain	0.8900
6:113859679:TTAGG:T	acceptor_gain	0.8900
6:113859680:TAGG:T	acceptor_gain	0.8900
6:113859681:AGGA:A	acceptor_gain	0.8900
6:113859682:GGAG:G	acceptor_gain	0.8900
6:113859301:G:GT	donor_gain	0.8800
6:113859220:GCCTT:G	donor_gain	0.8700
6:113859683:G:T	acceptor_gain	0.8700
6:113857863:G:GA	donor_gain	0.8600
6:113858861:G:T	donor_gain	0.8500
6:113857432:G:T	donor_gain	0.8100
6:113858861:G:GT	donor_gain	0.8100
6:113859198:G:T	donor_gain	0.8100
6:113858943:C:T	donor_gain	0.7900
6:113859678:CTTAG:C	acceptor_gain	0.7900

AlphaMissense

2115 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:113860052:T:C	F158L	1.000
6:113860053:T:C	F158S	1.000
6:113860053:T:G	F158C	1.000
6:113860054:T:A	F158L	1.000
6:113860054:T:G	F158L	1.000
6:113860059:T:C	F160S	1.000
6:113860059:T:G	F160C	1.000
6:113860061:A:G	K161E	1.000
6:113860063:G:C	K161N	1.000
6:113860063:G:T	K161N	1.000
6:113860070:T:C	F164L	1.000
6:113860071:T:C	F164S	1.000
6:113860072:C:A	F164L	1.000
6:113860072:C:G	F164L	1.000
6:113860073:A:G	K165E	1.000
6:113860077:T:A	L166Q	1.000
6:113860086:T:C	F169S	1.000
6:113860055:T:C	S159P	0.999
6:113860058:T:C	F160L	0.999
6:113860060:C:A	F160L	0.999
6:113860060:C:G	F160L	0.999
6:113860064:A:G	K162E	0.999
6:113860071:T:G	F164C	0.999
6:113860075:G:C	K165N	0.999
6:113860075:G:T	K165N	0.999
6:113860077:T:C	L166P	0.999
6:113860083:G:A	G168D	0.999
6:113860086:T:G	F169C	0.999
6:113860092:T:C	F171S	0.999
6:113860096:G:C	K172N	0.999

dbSNP variants (sampled 300 via entrez): RS1000003869 (6:113859420 C>A,T), RS1000062533 (6:113859863 GCCC>G,GCC,GCCCC), RS1000096795 (6:113859610 G>A,C), RS1000220930 (6:113863382 C>A,G), RS1001274333 (6:113860188 C>G,T), RS1002079205 (6:113855682 G>A,T), RS1002575393 (6:113858225 T>C,G), RS1002691398 (6:113858512 A>C,G), RS1002949568 (6:113861107 A>G), RS1002980655 (6:113860836 T>C), RS1003125758 (6:113856049 C>A,G), RS1003258402 (6:113863214 T>A), RS1003414751 (6:113857583 G>A,C), RS1003742757 (6:113862910 C>T), RS1004253375 (6:113859398 G>A,C)

Disease associations

OMIM: gene MIM:177061 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST002306_22	Bipolar disorder (body mass index interaction)	7.000000e-06
GCST002806_7	Type 2 diabetes	5.000000e-06
GCST003178_2	Event free survival in diffuse large B-cell lymphoma treated with immunochemotherapy	7.000000e-07
GCST009523_46	Household income	4.000000e-08
GCST009524_308	Household income (MTAG)	1.000000e-09
GCST011955_3	Alcohol dependence	6.000000e-06

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index
EFO:0000482	event free survival time
EFO:0007754	response to immunochemotherapy
EFO:0009695	household income

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4804244 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases expression, decreases methylation, increases expression, affects expression	5
bisphenol A	increases expression, affects cotreatment	4
Estradiol	affects cotreatment, decreases expression	3
Lipopolysaccharides	increases expression, affects expression, affects response to substance, affects cotreatment	3
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	3
bisphenol F	increases expression	2
S-(1,2-dichlorovinyl)cysteine	increases expression, affects cotreatment, decreases expression, affects response to substance	2
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	2
Gemcitabine	increases expression, increases phosphorylation	2
Air Pollutants	decreases expression, increases abundance	2
Benzo(a)pyrene	decreases methylation, increases expression, increases methylation	2
Dexamethasone	decreases expression, affects cotreatment, increases expression	2
Fluorouracil	decreases expression, affects response to substance	2
Progesterone	affects cotreatment, decreases expression	2
Tobacco Smoke Pollution	affects expression, decreases expression	2
aristolochic acid I	decreases expression	1
FR900359	decreases phosphorylation	1
testosterone enanthate	affects expression	1
methyleugenol	increases expression	1
triphenyl phosphate	affects expression	1
uranyl acetate	affects expression	1
deoxynivalenol	decreases expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, increases expression	1
methylparaben	decreases expression	1
sulforaphane	decreases expression	1
sodium arsenite	decreases expression	1
cobaltous chloride	decreases expression	1
4-O-methyl-12-O-tetradecanoylphorbol 13-acetate	increases phosphorylation	1
3,4,5,3’,4’-pentachlorobiphenyl	decreases expression	1
chloroquine diphosphate	decreases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5651759	Binding	Binding affinity to human MARCKS incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D2BT	Abcam HCT 116 MARCKS KO	Cancer cell line	Male
CVCL_D2NN	Abcam THP-1 MARCKS KO	Cancer cell line	Male

Clinical trials (associated diseases)

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