CMTM8

Summary

CMTM8 (CKLF like MARVEL transmembrane domain containing 8, HGNC:19179) is a protein-coding gene on chromosome 3p22.3, encoding CKLF-like MARVEL transmembrane domain-containing protein 8 (Q8IZV2).

This gene belongs to the chemokine-like factor gene superfamily, a novel family that is similar to the chemokine and the transmembrane 4 superfamilies. This gene is one of several chemokine-like factor genes located in a cluster on chromosome 3. This gene acts as a tumor suppressor, and plays a role in regulating the migration of tumor cells. The encoded protein is thought to function as a a negative regulator of epidermal growth factor-induced signaling. Alternative splicing results in multiple transcript variants encoding different isoforms.

Source: NCBI Gene 152189 — RefSeq curated summary.

At a glance

• GWAS associations: 5
• Clinical variants (ClinVar): 33 total
• MANE Select transcript: NM_178868

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:19179
Approved symbol	CMTM8
Name	CKLF like MARVEL transmembrane domain containing 8
Location	3p22.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000170293
Ensembl biotype	protein_coding
OMIM	607891
Entrez	152189

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 13 protein_coding

ENST00000307526, ENST00000458535, ENST00000867227, ENST00000867228, ENST00000867229, ENST00000867230, ENST00000867231, ENST00000867232, ENST00000867233, ENST00000867234, ENST00000867235, ENST00000867236, ENST00000867237

RefSeq mRNA: 2 — MANE Select: NM_178868 NM_001320308, NM_178868

CCDS: CCDS2652, CCDS82753

Canonical transcript exons

ENST00000307526 — 4 exons

Exon	Start	End
ENSE00001134584	32357373	32357546
ENSE00001141754	32367872	32367988
ENSE00001920321	32369884	32370321
ENSE00003844828	32238680	32239119

Expression profiles

Bgee: expression breadth ubiquitous, 204 present calls, max score 94.00.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 14.4725 / max 260.5570, expressed in 1505 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
35873	14.3075	1503
35872	0.1384	74
35874	0.0266	6

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	94.00	gold quality
body of pancreas	UBERON:0001150	92.41	gold quality
right lobe of liver	UBERON:0001114	91.80	gold quality
right lung	UBERON:0002167	91.77	gold quality
pancreatic ductal cell	CL:0002079	91.62	gold quality
oocyte	CL:0000023	91.55	gold quality
islet of Langerhans	UBERON:0000006	91.34	gold quality
pancreas	UBERON:0001264	91.26	gold quality
adrenal tissue	UBERON:0018303	89.37	gold quality
liver	UBERON:0002107	88.67	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	87.74	gold quality
ileal mucosa	UBERON:0000331	87.34	gold quality
upper lobe of left lung	UBERON:0008952	86.24	gold quality
upper lobe of lung	UBERON:0008948	86.03	gold quality
minor salivary gland	UBERON:0001830	85.49	gold quality
right adrenal gland	UBERON:0001233	85.05	gold quality
lower lobe of lung	UBERON:0008949	84.28	gold quality
right adrenal gland cortex	UBERON:0035827	84.01	gold quality
left adrenal gland	UBERON:0001234	83.60	gold quality
left lobe of thyroid gland	UBERON:0001120	83.40	gold quality
lung	UBERON:0002048	83.25	gold quality
body of stomach	UBERON:0001161	83.10	gold quality
omental fat pad	UBERON:0010414	82.98	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	82.92	gold quality
peritoneum	UBERON:0002358	82.91	gold quality
saliva-secreting gland	UBERON:0001044	82.86	gold quality
left adrenal gland cortex	UBERON:0035825	82.74	gold quality
adipose tissue of abdominal region	UBERON:0007808	82.41	gold quality
thyroid gland	UBERON:0002046	82.37	gold quality
subcutaneous adipose tissue	UBERON:0002190	82.36	gold quality

Single-cell (SCXA)

Detected in 7 experiment(s), a significant marker in 7.

Experiment	Marker?	Max mean expression
E-HCAD-56	yes	926.26
E-MTAB-5061	yes	214.58
E-CURD-112	yes	38.14
E-ANND-3	yes	15.18
E-MTAB-9067	yes	14.14
E-HCAD-31	yes	9.11
E-GEOD-83139	yes	4.80

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

30 targeting CMTM8, 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-3658	99.96	73.87	4379
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-450B-5P	99.92	71.48	3175
HSA-MIR-145-5P	99.92	71.13	1836
HSA-MIR-5195-3P	99.92	70.92	1877
HSA-MIR-374C-5P	99.80	72.06	2910
HSA-MIR-655-3P	99.80	72.19	2909
HSA-MIR-323A-3P	99.79	70.30	1739
HSA-MIR-6507-5P	99.36	70.46	2524
HSA-MIR-6853-3P	99.36	70.79	1558
HSA-MIR-16-2-3P	99.29	70.60	1954
HSA-MIR-195-3P	99.29	70.61	1954
HSA-MIR-3191-5P	99.24	66.52	1722
HSA-MIR-642A-3P	99.23	67.67	1258
HSA-MIR-642B-3P	99.23	67.67	1258
HSA-MIR-4528	99.18	69.77	1936
HSA-MIR-330-5P	98.73	67.63	1788
HSA-MIR-299-5P	98.56	71.14	1140
HSA-MIR-4766-3P	98.48	67.94	1347
HSA-MIR-5089-5P	98.45	66.06	1388
HSA-MIR-326	98.25	66.44	1565
HSA-MIR-3144-3P	98.15	67.34	677
HSA-MIR-12126	98.09	64.82	637
HSA-MIR-204-3P	97.80	66.84	1656
HSA-MIR-4799-3P	97.78	65.97	893
HSA-MIR-4646-5P	97.70	66.84	1692
HSA-MIR-4720-5P	97.46	65.67	893
HSA-MIR-5588-5P	97.46	65.70	913
HSA-MIR-3126-3P	97.17	66.51	468

Literature-anchored findings (GeneRIF, showing 15)

• Bioinformatics based on CKLF2 cDNA and protein sequences in combination with experimental validation identified CKLFSF1-8 gene clusters, between the SCY and the TM4SF gene families. The 8 family members were cloned and characterized. (PMID:12782130)
• These results identify CKLFSF8 as a novel regulator of EGF-induced signaling and indicate that the association of EGFR with four transmembrane proteins is critical for EGFR desensitization. (PMID:16263120)
• Cell proliferation and expression of EGFR of tumor cells can be inhibited by transfection of CKLFSF8. (PMID:16806010)
• These data implicate CMTM8 as a negative regulator of epidermal growth factor (EGF)-induced signaling. (PMID:17149703)
• The cloning and sequencing of an alternative splice form of CMTM8, obtained from a human blood cDNA library, that utilizes apoptotic pathways distinct from CMTM8, is reported. (PMID:17681841)
• Down-regulation of CMTM8 also promoted an epithelial mesenchymal transition-like change in MCF-10A cells, indicating a broader role for CMTM8 in regulating cellular transformation. (PMID:22337876)
• This study identified CMTM8 as a new candidate tumor suppressor gene and GPR177 as a new candidate oncogene in osteosarcoma. (PMID:25551557)
• overexpression of CMTM8 in bladder cancer results in reduced malignant cell growth, migration and invasion, which could make it a potential therapeutic target in the treatment of bladder cancer. (PMID:26503336)
• This is the first extensive study of CMTM8 expression in both normal and tumorous human tissues. Our findings strongly supported the potential role of CMTM8 as a novel tumor suppressor and may shape further functional studies on this gene (PMID:26574634)
• our data suggested that CMTM8 is an important tumor suppressor gene in human bladder cancer and qualified as a useful prognostic indicator for patients with bladder cancer. (PMID:26615421)
• CMTM8 Is a Suppressor of Human Mesenchymal Stem Cell Osteogenic Differentiation and Promoter of Proliferation Via EGFR Signaling. (PMID:32268840)
• Influence of CMTM8 polymorphisms on lung cancer susceptibility in the Chinese Han population. (PMID:33395025)
• Downregulated CMTM8 Correlates with Poor Prognosis in Gastric Cancer Patients. (PMID:33978454)
• MicroRNA-582-5p promotes triple-negative breast cancer invasion and metastasis by antagonizing CMTM8. (PMID:34978519)
• Identification and validation of EMT-immune-related prognostic biomarkers CDKN2A, CMTM8 and ILK in colon cancer. (PMID:35429970)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	cmtm8b	ENSDARG00000063162
danio_rerio	cmtm8a	ENSDARG00000102973
mus_musculus	Cmtm8	ENSMUSG00000041012
rattus_norvegicus	Cmtm8	ENSRNOG00000011201
caenorhabditis_elegans	F28H1.4	WBGENE00017909
caenorhabditis_elegans	F47B3.3	WBGENE00018527

Paralogs (14): CMTM1 (ENSG00000089505), CMTM6 (ENSG00000091317), PLP2 (ENSG00000102007), PLLP (ENSG00000102934), CMTM3 (ENSG00000140931), CMTM2 (ENSG00000140932), MALL (ENSG00000144063), MAL2 (ENSG00000147676), CMTM7 (ENSG00000153551), MARVELD1 (ENSG00000155254), CMTM5 (ENSG00000166091), MAL (ENSG00000172005), CMTM4 (ENSG00000183723), CKLF (ENSG00000217555)

Protein

Protein identifiers

CKLF-like MARVEL transmembrane domain-containing protein 8 — Q8IZV2 (reviewed: Q8IZV2)

Alternative names: Chemokine-like factor superfamily member 8

All UniProt accessions (1): Q8IZV2

UniProt curated annotations — full annotation on UniProt →

Subcellular location. Membrane Cytoplasm. Nucleus.

Tissue specificity. Highly expressed in liver and pancreas.

Similarity. Belongs to the chemokine-like factor family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q8IZV2-1	1	yes
Q8IZV2-2	2, CMTM8-v2

RefSeq proteins (2): NP_001307237, NP_849199* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR008253	Marvel	Domain
IPR013295	MAL	Family
IPR050578	MARVEL-CKLF_proteins	Family

Pfam: PF01284

UniProt features (10 total): transmembrane region 4, sequence conflict 3, chain 1, domain 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8IZV2-F1	77.37	0.32

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 88 (showing top): GOBP_TAXIS, LU_TUMOR_VASCULATURE_UP, GOBP_ENSHEATHMENT_OF_NEURONS, chr3p22, TURASHVILI_BREAST_DUCTAL_CARCINOMA_VS_DUCTAL_NORMAL_DN, GOMF_CYTOKINE_ACTIVITY, LASTOWSKA_NEUROBLASTOMA_COPY_NUMBER_DN, RYTTCCTG_ETS2_B, GOMF_SIGNALING_RECEPTOR_BINDING, NUYTTEN_EZH2_TARGETS_DN, GARY_CD5_TARGETS_UP, DODD_NASOPHARYNGEAL_CARCINOMA_DN, GOMF_SIGNALING_RECEPTOR_REGULATOR_ACTIVITY, GOMF_STRUCTURAL_MOLECULE_ACTIVITY, MEISSNER_BRAIN_HCP_WITH_H3K4ME3_AND_H3K27ME3

GO Biological Process (3): chemotaxis (GO:0006935), myelination (GO:0042552), signal transduction (GO:0007165)

GO Molecular Function (3): cytokine activity (GO:0005125), structural constituent of myelin sheath (GO:0019911), protein binding (GO:0005515)

GO Cellular Component (5): obsolete extracellular space (GO:0005615), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), membrane (GO:0016020), nucleus (GO:0005634)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
response to chemical	1
taxis	1
axon ensheathment	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
receptor ligand activity	1
structural molecule activity	1
myelin sheath	1
binding	1
nuclear lumen	1
intracellular anatomical structure	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

442 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CMTM8	CMTM7	Q96FZ5	977
CMTM8	CMTM6	Q9NX76	972
CMTM8	CKLF	Q9UBR5	939
CMTM8	CMTM3	Q96MX0	761
CMTM8	CMTM1	Q8IZ96	755
CMTM8	CMTM5	Q96DZ9	749
CMTM8	CMTM2	Q8TAZ6	740
CMTM8	MYADML2	A6NDP7	467
CMTM8	FRMD1	Q8N878	466
CMTM8	KASH5	Q8N6L0	445
CMTM8	TSPAN1	O60635	418
CMTM8	CMTM4	Q8IZR5	410
CMTM8	MOB3C	Q70IA8	397
CMTM8	GPRC5D	Q9NZD1	351
CMTM8	RRP8	O43159	348

IntAct

21 interactions, top by confidence:

A	B	Type	Score
KRTAP1-3	CMTM8	psi-mi:“MI:0915”(physical association)	0.560
CMTM8	TMEM14B	psi-mi:“MI:0915”(physical association)	0.560
CMTM8	EGFR	psi-mi:“MI:0915”(physical association)	0.560
CMTM8	EGFR	psi-mi:“MI:0403”(colocalization)	0.560
PDCD1	RTL8C	psi-mi:“MI:0914”(association)	0.530
ARMC6	SLC27A2	psi-mi:“MI:0914”(association)	0.530
CMTM8	UBXN8	psi-mi:“MI:0914”(association)	0.350
FFAR1	SLC12A8	psi-mi:“MI:0914”(association)	0.350
KLRB1	ESYT2	psi-mi:“MI:0914”(association)	0.350
ADAM7	RIOK3	psi-mi:“MI:0914”(association)	0.350
VSIG4	TNFRSF10B	psi-mi:“MI:0914”(association)	0.350
LRRC25	SCAMP3	psi-mi:“MI:0914”(association)	0.350
ICAM2	RAB29	psi-mi:“MI:0914”(association)	0.350
PRMT6	RAB29	psi-mi:“MI:0914”(association)	0.350
CMTM8	STX17	psi-mi:“MI:0914”(association)	0.350
CMTM8	KRTAP1-3	psi-mi:“MI:0915”(physical association)	0.000
CMTM8	TMEM14B	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (67): CMTM8 (Affinity Capture-RNA), CMTM8 (Affinity Capture-RNA), CMTM8 (Two-hybrid), KRTAP1-3 (Two-hybrid), COG6 (Affinity Capture-MS), TMEM242 (Affinity Capture-MS), SLC25A23 (Affinity Capture-MS), HIP1R (Affinity Capture-MS), KNTC1 (Affinity Capture-MS), MBOAT7 (Affinity Capture-MS), NR2F2 (Affinity Capture-MS), CHCHD6 (Affinity Capture-MS), ABHD17B (Affinity Capture-MS), MTFP1 (Affinity Capture-MS), DAGLB (Affinity Capture-MS)

ESM2 similar proteins: A4IFN5, A6NI61, A6QQ59, B0CM95, B2KI79, B2LYG4, B2RZC9, D0Q0Y7, O35089, P22234, P86229, Q15546, Q1RMP9, Q2TA01, Q3ZCD7, Q5BJU5, Q5QJU3, Q5R589, Q5RB59, Q5RDB5, Q5RL79, Q5U3C3, Q64232, Q6IQ69, Q6PHN7, Q6PI25, Q6ZWS4, Q719N3, Q865K8, Q86WK9, Q86YN1, Q8BWB6, Q8IY49, Q8IZV2, Q8N6L1, Q8N6M3, Q8NBT3, Q8NFT2, Q8R189, Q8TBE1

Diamond homologs: A3KQ86, A6H7B0, O09198, P21145, P47987, Q13021, Q1RMP9, Q28296, Q3ZBY0, Q64349, Q6GPN9, Q8IZV2, Q91X49, Q9CZR4, Q9DCU2, Q9Y342, Q8CJ61, A2VE13, Q5RAI2, Q8BI08, Q969L2, Q5BLB7

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	28
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

2370 predictions. Top by Δscore:

Variant	Effect	Δscore
3:32239074:G:GT	donor_gain	1.0000
3:32239116:GATC:G	donor_gain	1.0000
3:32239117:ATC:A	donor_gain	1.0000
3:32239118:TC:T	donor_gain	1.0000
3:32239120:G:GG	donor_gain	1.0000
3:32239115:AGATC:A	donor_gain	0.9900
3:32239116:GATCG:G	donor_gain	0.9900
3:32239117:ATCG:A	donor_loss	0.9900
3:32239118:TCG:T	donor_loss	0.9900
3:32239119:CG:C	donor_loss	0.9900
3:32239120:GTGA:G	donor_loss	0.9900
3:32239121:TGAG:T	donor_loss	0.9900
3:32239122:GAGT:G	donor_loss	0.9900
3:32282578:T:G	acceptor_gain	0.9900
3:32290603:GC:G	donor_gain	0.9900
3:32357544:GTG:G	donor_gain	0.9900
3:32367989:GTG:G	donor_loss	0.9900
3:32367990:T:A	donor_loss	0.9900
3:32367991:GAGTA:G	donor_loss	0.9900
3:32369882:A:AG	acceptor_gain	0.9900
3:32369883:G:GG	acceptor_gain	0.9900
3:32239123:AGTGC:A	donor_loss	0.9800
3:32249058:T:A	acceptor_gain	0.9800
3:32280669:A:AG	acceptor_gain	0.9800
3:32280683:A:AG	acceptor_gain	0.9800
3:32280684:G:GG	acceptor_gain	0.9800
3:32367907:C:G	acceptor_gain	0.9800
3:32367989:G:GG	donor_gain	0.9800
3:32369883:GTT:G	acceptor_gain	0.9800
3:32283625:G:GT	donor_gain	0.9700

AlphaMissense

1131 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:32357391:T:A	W56R	1.000
3:32357391:T:C	W56R	1.000
3:32367890:A:C	S114R	1.000
3:32367892:T:A	S114R	1.000
3:32367892:T:G	S114R	1.000
3:32357379:G:A	G52R	0.999
3:32357379:G:C	G52R	0.999
3:32357379:G:T	G52W	0.999
3:32357380:G:A	G52E	0.999
3:32357398:T:C	L58P	0.999
3:32357439:T:A	W72R	0.999
3:32357439:T:C	W72R	0.999
3:32357454:G:C	A77P	0.999
3:32357466:T:A	W81R	0.999
3:32357466:T:C	W81R	0.999
3:32357476:C:T	T84I	0.999
3:32357535:T:A	W104R	0.999
3:32357535:T:C	W104R	0.999
3:32357537:G:C	W104C	0.999
3:32357537:G:T	W104C	0.999
3:32367894:C:A	A115D	0.999
3:32239096:G:C	G42R	0.998
3:32357380:G:T	G52V	0.998
3:32357398:T:A	L58H	0.998
3:32357404:C:A	A60D	0.998
3:32357410:C:T	T62I	0.998
3:32357448:T:C	F75L	0.998
3:32357450:T:A	F75L	0.998
3:32357450:T:G	F75L	0.998
3:32367915:C:A	A122D	0.998

dbSNP variants (sampled 300 via entrez): RS1000017882 (3:32293985 G>A), RS1000026099 (3:32352631 G>A), RS1000069770 (3:32312242 A>G), RS1000099266 (3:32325391 G>A), RS1000102847 (3:32365635 G>A,C), RS1000131200 (3:32307839 A>T), RS1000152384 (3:32277964 T>C), RS1000190312 (3:32356184 T>G), RS1000204403 (3:32255821 G>T), RS1000225788 (3:32357775 T>C), RS1000228056 (3:32277584 G>A), RS1000231778 (3:32317146 C>T), RS1000266292 (3:32339502 A>G), RS1000370418 (3:32237933 G>A,C), RS1000389831 (3:32319795 C>A)

Disease associations

OMIM: gene MIM:607891 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST001352_9	HIV-1 viral setpoint	5.000000e-06
GCST002312_8	Periodontal disease-related phenotype (Socransky)	6.000000e-06
GCST004212_12	Height	2.000000e-08
GCST009675_3	Urinary magnesium excretion	1.000000e-06
GCST012174_1	Diabetic retinopathy in type 2 diabetes	7.000000e-10

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0006319	HIV viral set point measurement
EFO:0004845	magnesium measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs4627790	Efficacy	3	methylphenidate	Attention Deficit Disorder with Hyperactivity

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs4627790	CMTM8	3	0.00	1	methylphenidate

CTD chemical–gene interactions

29 total (human), top 29 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases expression	5
Aflatoxin B1	decreases expression, decreases methylation, affects expression	3
bisphenol A	affects expression, affects methylation	2
Benzo(a)pyrene	decreases expression, decreases methylation	2
Cyclosporine	increases expression	2
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
pirinixic acid	affects binding, decreases expression, increases activity	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
ochratoxin A	increases acetylation	1
aflatoxin B2	increases methylation	1
CGP 52608	affects binding, increases reaction	1
entinostat	increases expression	1
K 7174	increases expression	1
abrine	decreases expression	1
gardiquimod	increases expression, decreases reaction	1
Temozolomide	increases expression	1
Sunitinib	increases expression	1
Arsenic Trioxide	decreases expression	1
Arsenic	affects expression	1
Atrazine	increases expression	1
Cisplatin	decreases expression	1
Coumestrol	decreases expression	1
Estradiol	affects cotreatment, decreases expression	1
Sodium Dodecyl Sulfate	decreases expression	1
Tobacco Smoke Pollution	increases expression	1
Vanadates	decreases expression	1
Lactic Acid	decreases expression	1
Protein Kinase Inhibitors	decreases reaction, increases expression	1

Clinical trials (associated diseases)

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