CAB39

Summary

CAB39 (calcium binding protein 39, HGNC:20292) is a protein-coding gene on chromosome 2q37.1, encoding Calcium-binding protein 39 (Q9Y376). Component of a complex that binds and activates STK11/LKB1. It is a selective cancer dependency (DepMap: 23.1% of cell lines).

Enables protein serine/threonine kinase activator activity and protein serine/threonine kinase binding activity. Involved in cellular hypotonic response; intracellular signal transduction; and negative regulation of potassium ion transmembrane transport. Located in cytoplasm. Part of serine/threonine protein kinase complex. Implicated in hepatocellular carcinoma. Biomarker of hepatocellular carcinoma and pancreatic cancer.

Source: NCBI Gene 51719 — automated summary from GO annotations (Alliance of Genome Resources).

At a glance

• Clinical variants (ClinVar): 28 total — 1 pathogenic
• GTEx eGene: eQTL in 12 tissues, sQTL in 2 (q < 0.05)
• Cancer dependency (DepMap): dependent in 23.1% of screened cell lines
• Constraint (gnomAD): pLI 0.67 (intermediate), LOEUF 0.69 (unconstrained)
• MANE Select transcript: NM_016289

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:20292
Approved symbol	CAB39
Name	calcium binding protein 39
Location	2q37.1
Locus type	gene with protein product
Status	Approved
Aliases	CGI-66, MO25
Ensembl gene	ENSG00000135932
Ensembl biotype	protein_coding
OMIM	612174
Entrez	51719

Gene structure

Transcript identifiers

Ensembl transcripts: 36 — 27 protein_coding, 6 nonsense_mediated_decay, 2 retained_intron, 1 protein_coding_CDS_not_defined

MANE Select: ENST00000258418

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 2, TSL 2: 2, TSL 4: 2

ENST00000258418, ENST00000409788, ENST00000410084, ENST00000478152, ENST00000484398, ENST00000493540, ENST00000874559, ENST00000874560, ENST00000874561, ENST00000874562, ENST00000874563, ENST00000874564, ENST00000874565, ENST00000874566, ENST00000874567, ENST00000874568, ENST00000874569, ENST00000874570, ENST00000913362, ENST00000913363, ENST00000913364, ENST00000913365, ENST00000913366, ENST00000962335, ENST00000962336, ENST00000962337, ENST00000962338, ENST00000962339, ENST00000974822, ENST00001051542, ENST00001051544, ENST00001051545, ENST00001051546, ENST00001051547, ENST00001118937, ENST00001140797

RefSeq mRNA: 3 — MANE Select: NM_016289 NM_001130849, NM_001130850, NM_016289

CCDS: CCDS2478

Canonical transcript exons

ENST00000258418 — 9 exons

Exon	Start	End
ENSE00000922487	230790872	230791036
ENSE00000922489	230810263	230810322
ENSE00000922490	230814049	230814114
ENSE00000965552	230798729	230798897
ENSE00001154635	230712842	230713230
ENSE00001174706	230818516	230821075
ENSE00001174710	230759959	230760115
ENSE00001722339	230817754	230817897
ENSE00003504728	230793213	230793331

Expression profiles

Bgee: expression breadth ubiquitous, 292 present calls, max score 98.86.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 37.1960 / max 387.5476, expressed in 1822 samples.

Highest expression (Bgee): amniotic fluid, esophagus squamous epithelium, tibia, middle temporal gyrus, skeletal muscle tissue of rectus abdominis.

Genetic regulation across tissues (GTEx eQTL / sQTL)

CAB39 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 12 tissues and its splicing (sQTL) in 2 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

14 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Muscle Skeletal	eqtl	3.8e-12	-0.20	2:230669201:A:G
Esophagus Mucosa	eqtl	5.5e-06	-0.12	2:230818772:CTT:C
Thyroid	eqtl	7.8e-06	-0.16	2:230818223:T:C
Whole Blood	eqtl	2.9e-05	-0.06	2:230822245:G:A
Lung	eqtl	4.6e-05	-0.16	2:230749111:C:T
Testis	eqtl	8.1e-05	-0.14	2:230822245:G:A
Skin Not Sun Exposed Suprapubic	eqtl	1.3e-04	-0.12	2:230806701:C:G
Pituitary	eqtl	1.6e-04	-0.24	2:230721324:A:G
Stomach	eqtl	7.4e-03	-0.70	2:231469687:C:T
Skin Sun Exposed Lower leg	eqtl	1.6e-02	+0.13	2:230739635:C:T
Cells EBV-transformed lymphocytes	eqtl	3.2e-02	-0.16	2:230838382:CTA:C
Brain Putamen basal ganglia	eqtl	3.7e-02	-0.12	2:229804266:T:G
Testis	sqtl	4.6e-02	-0.36	2:230588916:T:A
Brain Cortex	sqtl	5.0e-02	-2.43	2:230343479:A:G

FANTOM5 promoters

4 alternative TSS:

Promoter ID	TPM avg	Samples expressed
25822	34.4618	1820
25826	1.4704	714
25823	1.2121	514
25825	0.0518	22

Top tissues by expression

showing 100 of 292 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
amniotic fluid	UBERON:0000173	98.86	gold quality
esophagus squamous epithelium	UBERON:0006920	98.82	gold quality
tibia	UBERON:0000979	98.32	gold quality
middle temporal gyrus	UBERON:0002771	98.31	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	98.16	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	98.13	gold quality
biceps brachii	UBERON:0001507	97.98	gold quality
mucosa of sigmoid colon	UBERON:0004993	97.86	gold quality
palpebral conjunctiva	UBERON:0001812	97.83	gold quality
gluteal muscle	UBERON:0002000	97.75	gold quality
colonic mucosa	UBERON:0000317	97.73	gold quality
cartilage tissue	UBERON:0002418	97.69	gold quality
epithelium of esophagus	UBERON:0001976	97.52	gold quality
triceps brachii	UBERON:0001509	97.26	gold quality
eye	UBERON:0000970	97.11	gold quality
medial globus pallidus	UBERON:0002477	97.11	gold quality
squamous epithelium	UBERON:0006914	97.08	gold quality
oral cavity	UBERON:0000167	96.94	gold quality
skeletal muscle tissue	UBERON:0001134	96.89	gold quality
trabecular bone tissue	UBERON:0002483	96.88	gold quality
muscle of leg	UBERON:0001383	96.79	gold quality
muscle organ	UBERON:0001630	96.72	gold quality
skeletal muscle organ	UBERON:0014892	96.72	gold quality
gastrocnemius	UBERON:0001388	96.71	gold quality
epithelium of nasopharynx	UBERON:0001951	96.71	gold quality
hindlimb stylopod muscle	UBERON:0004252	96.70	gold quality
vastus lateralis	UBERON:0001379	96.64	gold quality
pons	UBERON:0000988	96.62	gold quality
visceral pleura	UBERON:0002401	96.60	gold quality
jejunal mucosa	UBERON:0000399	96.59	gold quality
monocyte	CL:0000576	96.51	gold quality
mononuclear cell	CL:0000842	96.48	gold quality
Brodmann (1909) area 46	UBERON:0006483	96.48	gold quality
leukocyte	CL:0000738	96.44	gold quality
orbitofrontal cortex	UBERON:0004167	96.43	gold quality
rectum	UBERON:0001052	96.42	gold quality
tongue squamous epithelium	UBERON:0006919	96.34	gold quality
diaphragm	UBERON:0001103	96.28	gold quality
globus pallidus	UBERON:0001875	96.22	gold quality
pleura	UBERON:0000977	96.14	gold quality
quadriceps femoris	UBERON:0001377	96.05	gold quality
nephron tubule	UBERON:0001231	96.04	gold quality
vermiform appendix	UBERON:0001154	96.02	gold quality
body of tongue	UBERON:0011876	96.01	gold quality
jejunum	UBERON:0002115	96.00	gold quality
cortical plate	UBERON:0005343	95.98	gold quality
blood	UBERON:0000178	95.95	gold quality
gingiva	UBERON:0001828	95.93	gold quality
bronchial epithelial cell	CL:0002328	95.86	gold quality
muscle tissue	UBERON:0002385	95.84	gold quality
parietal pleura	UBERON:0002400	95.84	gold quality
postcentral gyrus	UBERON:0002581	95.80	gold quality
dorsal root ganglion	UBERON:0000044	95.76	gold quality
metanephric glomerulus	UBERON:0004736	95.75	gold quality
bone marrow	UBERON:0002371	95.74	gold quality
epithelium of bronchus	UBERON:0002031	95.69	gold quality
renal glomerulus	UBERON:0000074	95.67	gold quality
caput epididymis	UBERON:0004358	95.67	gold quality
tibialis anterior	UBERON:0001385	95.66	gold quality
duodenum	UBERON:0002114	95.66	gold quality
tongue	UBERON:0001723	95.65	gold quality
gingival epithelium	UBERON:0001949	95.64	gold quality
bronchus	UBERON:0002185	95.60	gold quality
Brodmann (1909) area 23	UBERON:0013554	95.58	gold quality
tendon	UBERON:0000043	95.52	gold quality
heart right ventricle	UBERON:0002080	95.49	gold quality
parietal lobe	UBERON:0001872	95.47	gold quality
superior frontal gyrus	UBERON:0002661	95.45	gold quality
deltoid	UBERON:0001476	95.44	gold quality
pharyngeal mucosa	UBERON:0000355	95.40	gold quality
smooth muscle tissue	UBERON:0001135	95.38	gold quality
upper leg skin	UBERON:0004262	95.38	gold quality
skin of hip	UBERON:0001554	95.29	gold quality
lymph node	UBERON:0000029	95.28	gold quality
secondary oocyte	CL:0000655	95.27	gold quality
gall bladder	UBERON:0002110	95.27	gold quality
tonsil	UBERON:0002372	95.23	gold quality
caecum	UBERON:0001153	95.20	gold quality
calcaneal tendon	UBERON:0003701	95.13	gold quality
bone marrow cell	CL:0002092	95.00	gold quality
superior surface of tongue	UBERON:0007371	94.99	gold quality
tendon of biceps brachii	UBERON:0008188	94.95	gold quality
popliteal artery	UBERON:0002250	94.94	gold quality
tibial artery	UBERON:0007610	94.94	gold quality
prefrontal cortex	UBERON:0000451	94.93	gold quality
superior vestibular nucleus	UBERON:0007227	94.88	gold quality
urinary bladder	UBERON:0001255	94.86	gold quality
ganglionic eminence	UBERON:0004023	94.82	gold quality
cauda epididymis	UBERON:0004360	94.81	gold quality
occipital lobe	UBERON:0002021	94.79	gold quality
primary visual cortex	UBERON:0002436	94.79	gold quality
endothelial cell	CL:0000115	94.77	gold quality
mammalian vulva	UBERON:0000997	94.74	gold quality
periodontal ligament	UBERON:0008266	94.67	gold quality
saphenous vein	UBERON:0007318	94.66	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	94.65	gold quality
aorta	UBERON:0000947	94.63	gold quality
parotid gland	UBERON:0001831	94.63	gold quality
lower lobe of lung	UBERON:0008949	94.58	gold quality
pigmented layer of retina	UBERON:0001782	94.51	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-CURD-119	yes	32.03
E-ANND-3	yes	9.86

HPA expression

RNA tissue specificity: Tissue enhanced

showing 60 of 79 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Skeletal muscle	tissue	168.0	high
Frontal cortex	tissue	115.5
Tongue	tissue	111.3
Caudate putamen	tissue	110.0
Thalamus	tissue	85.8
Pons	tissue	82.2
Spinal cord	tissue	81.4
Midbrain	tissue	80.2
Cerebral cortex	tissue	78.6	high
Superior colliculi	tissue	78.6
Somatosensory cortex	tissue	78.6
Occipital cortex	tissue	74.6
Medulla oblongata	tissue	73.9
Motor cortex	tissue	71.6
Substantia nigra	tissue	70.3
Putamen	tissue	68.2
Hippocampal formation	tissue	66.6
Locus coeruleus	tissue	64.1
Prefrontal cortex	tissue	63.8
Postcentral gyrus	tissue	63.0
Entorhinal cortex	tissue	62.4
Periaqueductal gray	tissue	61.5
Hypothalamus	tissue	61.3
Corpus callosum	tissue	61.3
Temporal cortex	tissue	60.9
Retrosplenial and cingulate cortex	tissue	60.3
Septum	tissue	59.8
Retrosplenial cortex	tissue	57.6
Cerebellum	tissue	57.1	high
Ventral forebrain	tissue	56.4
Tonsil	tissue	52.8	medium
Hippocampus	tissue	52.4	medium
Lymph node	tissue	52.1	medium
Olfactory bulb	tissue	51.6
Choroid plexus	tissue	51.4
Insular cortex	tissue	50.8
Esophagus	tissue	49.9	medium
Kidney	tissue	49.8	medium
Heart muscle	tissue	49.4	medium
Appendix	tissue	49.4	medium
Rectum	tissue	48.9	medium
Colon	tissue	48.9	medium
Basal ganglia	tissue	48.2	medium
Amygdala	tissue	47.6
Small intestine	tissue	47.1	medium
Nucleus accumbens	tissue	46.0
Bone marrow	tissue	45.6	medium
Urinary bladder	tissue	45.2	medium
Duodenum	tissue	43.6	medium
Stomach 1	tissue	42.8	medium
Thymus	tissue	40.7
Adipose tissue	tissue	39.5	low
Parathyroid gland	tissue	38.8	low
Retina	tissue	37.9
Gallbladder	tissue	37.4	medium
Prostate	tissue	37.4	medium
Testis	tissue	36.4	high
Lung	tissue	36.3	medium
Spleen	tissue	35.6	medium
Liver	tissue	34.5	not detected

Brain sub-regions (HPA Brain Atlas): detected in 192; highest nTPM — Ventral spinal cord (81.4), Lateral funiculus (white matter) (74.8), Anterior funiculus (white matter) (69.3), Precentral gyrus, middle (68.8), Pontine nuclei (68.0).

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

Targeting CAB39 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 162 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
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-190A-3P	100.00	80.35	5520
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-223-3P	99.99	70.14	1140
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-3617-3P	99.98	67.86	918
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-1468-3P	99.96	72.74	3797

Functional genomics

gnomAD constraint: pLI 0.675, LOEUF 0.693, missense Z 2.11 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000258418 — one region, missense o/e 0.67. DepMap (CRISPR cell-line fitness): dependent in 23.1% of screened cell lines.

Most-dependent cell lines (DepMap gene-effect, lower = stronger; ≤ −0.5 shown): SNU-16 (-1.764), Mero-25 (-1.641), MGH-ICC4 (-1.556), M104325 (-1.542), SNU-601 (-1.527), COV413A (-1.514), COLO 824 (-1.499), HCC1806 (-1.437), DMS 53 (-1.437), 697 (-1.436), SNU-620 (-1.37), JHU-022 (-1.369), KCL-22 (-1.366), NCI-H1694 (-1.328), SK-MM-2 (-1.313).

Literature-anchored findings (GeneRIF, showing 15)

• STRADalpha.MO25alpha complexes containing LKB1 variants were equally effective at phosphorylating and activating AMPK, BRSK1, and BRSK2 (PMID:18854318)
• These data define a brush border induction pathway downstream of the Lkb1/Strad/Mo25 polarization complex, yet separate from other polarity events. (PMID:19386264)
• ATP and MO25alpha cooperate to maintain STRADalpha in an “active” closed conformation required for LKB1 activation. (PMID:19513107)
• study describes structure of the core heterotrimeric LKB1-STRADalpha-MO25alpha complex, revealing an unusual allosteric mechanism of LKB1 activation; structure also reveals how mutations in Peutz-Jeghers syndrome & sporadic cancers impair LKB1 function (PMID:19892943)
• MO25 is a master regulator of SPAK/OSR1 and MST3/MST4/YSK1 protein kinases. (PMID:21423148)
• Authors conclude that miR-451 represses glioma in vitro and in vivo, likely through targeting CAB39 directly and inhibiting the PI3K/AKT pathway indirectly. (PMID:22179124)
• These data provide molecular understanding of the mechanism by which MO25 isoforms regulates the activity of STE20 family protein kinases. (PMID:23296203)
• plays very important oncogenic roles in hepatocellular carcinoma pathogenesis and progression by activating the ERK signaling pathway (PMID:28605041)
• The MO25 binding to SPAK and OSR1 is enhanced by serine phosphorylation in their highly conserved WEWS motif, which is located in their C-terminal domains. (PMID:30060950)
• Upregulation of miR-451 expression suppressed the growth and invasion of glioma cells in vitro and in vivo by targeting CAB39 and modulating the mTOR/HIF-1a/VEGF signaling pathway. (PMID:30180756)
• miR-1265 suppresses gastric cancer progression and oncogenic autophagy by reducing CAB39 expression and regulating the AMPK-mTOR signaling pathway. (PMID:30779944)
• MiR-107 confers chemoresistance to colorectal cancer by targeting calcium-binding protein 39. (PMID:31919406)
• miR-107 inhibition upregulates CAB39 and activates AMPK-Nrf2 signaling to protect osteoblasts from dexamethasone-induced oxidative injury and cytotoxicity. (PMID:32527986)
• CAB39 promotes cisplatin resistance in bladder cancer via the LKB1-AMPK-LC3 pathway. (PMID:37726090)
• miR-451a was selectively sorted into exosomes and promoted the progression of esophageal squamous cell carcinoma through CAB39. (PMID:38649419)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	cab39	ENSDARG00000043451
mus_musculus	Cab39	ENSMUSG00000036707
rattus_norvegicus	Cab39	ENSRNOG00000017297
drosophila_melanogaster	Mo25	FBGN0017572
caenorhabditis_elegans		WBGENE00013140
caenorhabditis_elegans		WBGENE00019827

Paralogs (1): CAB39L (ENSG00000102547)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:107438) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 11 distinct phenotype terms.

Mouse phenotype (MP)	Records
increased monocyte cell number	1
decreased leukocyte cell number	1
abnormal embryo size	1
short tibia	1
abnormal forebrain development	1
abnormal neural tube closure	1
abnormal midbrain development	1
decreased lymphocyte cell number	1
increased blood urea nitrogen level	1
abnormal hindbrain development	1
preweaning lethality, complete penetrance	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Bos taurus	Q29RI6	100.0%	Diamond
Arabidopsis thaliana	Q9FGK3	87.2%	Diamond
Auxenochlorella protothecoides	Q9XFY6	52.0%	Diamond
Schizosaccharomyces pombe 972h-	Q9P7Q8	51.5%	Diamond
Aspergillus nidulans FGSC A4	O60032	40.1%	Diamond
Saccharomyces cerevisiae S288C	P32464	33.2%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
LINC01907	ncRNA	151475
ITM2C	protein-coding	81618
GCSIR	ncRNA	151484
SP100	protein-coding	6672
GPR55	protein-coding	9290
SPATA3-AS1	ncRNA	348761

Protein

Protein identifiers

Calcium-binding protein 39 — Q9Y376 (reviewed: Q9Y376)

Alternative names: MO25alpha, Protein Mo25

All UniProt accessions (1): Q9Y376

UniProt curated annotations — full annotation on UniProt →

Function. Component of a complex that binds and activates STK11/LKB1. In the complex, required to stabilize the interaction between CAB39/MO25 (CAB39/MO25alpha or CAB39L/MO25beta) and STK11/LKB1.

Subunit / interactions. Component of a trimeric complex composed of STK11/LKB1, STRAD (STRADA or STRADB) and CAB39/MO25 (CAB39/MO25alpha or CAB39L/MO25beta): the complex tethers STK11/LKB1 in the cytoplasm and stimulates its catalytic activity.

Subcellular location. Cytoplasm.

Similarity. Belongs to the Mo25 family.

RefSeq proteins (3): NP_001124321, NP_001124322, NP_057373* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR011989	ARM-like	Homologous_superfamily
IPR013878	Mo25	Family
IPR016024	ARM-type_fold	Homologous_superfamily

Pfam: PF08569

UniProt features (33 total): helix 27, mutagenesis site 2, turn 2, chain 1, strand 1

Structure

Experimental structures (PDB)

10 structures by resolution:

PDB	Title	Method	Resolution (Å)
1UPK	Crystal structure of MO25 in complex with a C-terminal peptide of STRAD	X-RAY DIFFRACTION	1.85
3GNI	Structure of STRAD and MO25	X-RAY DIFFRACTION	2.35
1UPL	Crystal structure of MO25 alpha	X-RAY DIFFRACTION	2.6
2WTK	Structure of the heterotrimeric LKB1-STRADalpha-MO25alpha complex	X-RAY DIFFRACTION	2.65
8VSU	Cryo-EM structure of LKB1-STRADalpha-MO25alpha heterocomplex	ELECTRON MICROSCOPY	2.86
4FZA	Crystal structure of MST4-MO25 complex	X-RAY DIFFRACTION	3.15
4O27	Crystal structure of MST3-MO25 complex with WIF motif	X-RAY DIFFRACTION	3.19
4FZD	Crystal structure of MST4-MO25 complex with WSF motif	X-RAY DIFFRACTION	3.25
4NZW	Crystal Structure of STK25-MO25 Complex	X-RAY DIFFRACTION	3.58
4FZF	Crystal structure of MST4-MO25 complex with DKI	X-RAY DIFFRACTION	3.64

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y376-F1	94.77	0.92

Human Protein Atlas

Protein class: Predicted intracellular proteins, Plasma proteins

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): vesicles; endoplasmic reticulum

Antibody reliability (HPA): IH approved · IF approved

Functional residue map

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

Mutagenesis-validated functional residues (2)

Position	Phenotype
240	abolishes activation of stk11/lkb1; when associated with a-243.
243	abolishes activation of stk11/lkb1; when associated with a-240.

Function

Pathways and Gene Ontology

Reactome pathways

2 curated (TAS) of 6; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

6 pathways:

ID	Pathway	Evidence
R-HSA-380972	Energy dependent regulation of mTOR by LKB1-AMPK	curated
R-HSA-6798695	Neutrophil degranulation	curated
R-HSA-168256	Immune System	—
R-HSA-168249	Innate Immune System	—
R-HSA-165159	MTOR signalling	—
R-HSA-162582	Signal Transduction	—

MSigDB gene sets: 279 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_DN, GOBP_POTASSIUM_ION_TRANSPORT, GOBP_NEGATIVE_REGULATION_OF_TRANSMEMBRANE_TRANSPORT, REACTOME_INNATE_IMMUNE_SYSTEM, TGCGCANK_UNKNOWN, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, GOCC_SECRETORY_GRANULE, CHIANG_LIVER_CANCER_SUBCLASS_UNANNOTATED_DN, KYNG_DNA_DAMAGE_DN, GOBP_MONOATOMIC_CATION_TRANSPORT, GOMF_KINASE_ACTIVATOR_ACTIVITY, GOBP_NEGATIVE_REGULATION_OF_TRANSPORT, CATTTCA_MIR203, GOBP_NEGATIVE_REGULATION_OF_POTASSIUM_ION_TRANSPORT, MODULE_239

GO Biological Process (6): signal transduction (GO:0007165), response to activity (GO:0014823), intracellular signal transduction (GO:0035556), cellular hypotonic response (GO:0071476), response to thyroid hormone (GO:0097066), negative regulation of potassium ion transmembrane transport (GO:1901380)

GO Molecular Function (5): kinase binding (GO:0019900), protein kinase activator activity (GO:0030295), protein serine/threonine kinase activator activity (GO:0043539), protein serine/threonine kinase binding (GO:0120283), protein binding (GO:0005515)

GO Cellular Component (9): extracellular region (GO:0005576), cytoplasm (GO:0005737), cytosol (GO:0005829), Z disc (GO:0030018), secretory granule lumen (GO:0034774), extracellular exosome (GO:0070062), serine/threonine protein kinase complex (GO:1902554), ficolin-1-rich granule lumen (GO:1904813), protein-containing complex (GO:0032991)

Reactome top-level categories

4 top-level categories:

Category	Pathways
MTOR signalling	1
Innate Immune System	1
Signal Transduction	1
Immune System	1

GO top-level categories

33 GO namespaces:

Category	Terms
cellular anatomical structure	4
intracellular anatomical structure	2
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
response to stimulus	1
signal transduction	1
hypotonic response	1
cellular response to osmotic stress	1
response to hormone	1
negative regulation of potassium ion transport	1
potassium ion transmembrane transport	1
regulation of potassium ion transmembrane transport	1
negative regulation of cation transmembrane transport	1
enzyme binding	1
protein kinase activity	1
kinase activator activity	1
protein kinase regulator activity	1
protein serine/threonine kinase activity	1
protein kinase activator activity	1
protein kinase binding	1
binding	1
cytoplasm	1
I band	1
secretory granule	1
cytoplasmic vesicle lumen	1
extracellular vesicle	1
protein kinase complex	1
intracellular organelle lumen	1
ficolin-1-rich granule	1
cellular_component	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 11 of 20 annotations. The rest are phylogenetic / computational / electronic (IEA).

11 experimentally-supported GO terms:

GO term	NS	Evidence
cellular hypotonic response	BP	direct assay
intracellular signal transduction	BP	direct assay
negative regulation of potassium ion transmembrane transport	BP	direct assay
signal transduction	BP	direct assay
cytoplasm	CC	direct assay
extracellular exosome	CC	high-throughput assay
serine/threonine protein kinase complex	CC	direct assay
kinase binding	MF	physical interaction
protein kinase activator activity	MF	direct assay
protein serine/threonine kinase activator activity	MF	direct assay
protein serine/threonine kinase binding	MF	physical interaction

Protein interactions and networks

STRING

showing 15 of 1,132 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CAB39	STRADA	Q7RTN6	979
CAB39	STK11	Q15831	936
CAB39	STRADB	Q9C0K7	849
CAB39	SNRK	Q9NRH2	796
CAB39	STK24	Q9Y6E0	752
CAB39	STK25	O00506	686
CAB39	STK39	Q9UEW8	619
CAB39	STK26	Q9P289	583
CAB39	DUSP5	Q16690	554
CAB39	HEY2	Q9UBP5	554
CAB39	CAMKK2	Q96RR4	547
CAB39	OXSR1	O95747	494
CAB39	STK11IP	Q8N1F8	467
CAB39	WNK4	Q96J92	456
CAB39	BRSK1	Q8TDC3	454

IntAct

Human interaction partners of CAB39 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

23 partners by confidence:

Partner	Interaction type	MIscore	Records
STK11	physical association	0.950	8
STRADB	physical association	0.770	5
STK25	physical association	0.740	3
STRADA	direct interaction	0.730	10
STK26	direct interaction	0.690	16
CEP44	physical association	0.560	3
GOLGA2	physical association	0.560	3
MCCD1	physical association	0.560	3
MED7	physical association	0.560	3
SHMT2	physical association	0.560	3
STK24	physical association	0.560	3
STK39	direct interaction	0.540	4
OXSR1	direct interaction	0.440	3
EEF1A2	association	0.350	1
BCKDK	physical association	0.000	1
CUL2	physical association	0.000	1
EBLN2	physical association	0.000	1
IPO5	physical association	0.000	1
MOB4	physical association	0.000	1
RAD51	physical association	0.000	1
RSL1D1	physical association	0.000	1
TIMM13	physical association	0.000	1
VHL	physical association	0.000	1

BioGRID (114 interactions; top human partners by supporting records): STK11 (Affinity Capture-MS; 18 records), STRADA (Co-crystal Structure; 4 records), STRADB (Affinity Capture-MS; 4 records), CAB39L (Affinity Capture-MS; 3 records), STK25 (Affinity Capture-MS; 3 records), C5orf24 (Affinity Capture-MS; 2 records), CYP1A1 (Affinity Capture-MS; 2 records), PIP4K2A (Affinity Capture-MS; 2 records), VHL (Affinity Capture-MS; 2 records), AHCYL2 (Affinity Capture-MS), AP2B1 (Co-fractionation), BBS1 (Affinity Capture-MS), BCKDK (Affinity Capture-MS), C12orf49 (Positive Genetic), CDK7 (Affinity Capture-MS)

Protein complexes (CORUM) (1)

Experimentally-characterized complexes this protein is a subunit of (★ = the complex contains a known drug target).

1 complexes by size:

Complex	Subunits	Members
LKB1-STRAD-MO25 complex	3	CAB39, STK11, STRADA

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 23 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.

GO biological processes:

GO term	Partners	Fold	FDR
protein autophosphorylation	6	41.5×	1e-06
protein phosphorylation	6	19.4×	3e-05
intracellular signal transduction	5	9.1×	3e-03

Disease & clinical

Genetic variants

Variant evidence for CAB39: 28 ClinVar records (1 pathogenic / likely pathogenic). Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	13
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (1)

Showing all 1 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
1526961	GRCh37/hg19 2q36.3-37.1(chr2:229968217-231883182)x1	Pathogenic	criteria provided, single submitter	1

Per-variant reference — Sugi Variant

Explore CAB39’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 43 predictions of 1,012):

Position(s)	Effect	Δscore	Sites
2:230759957–230759958	acceptor_loss	1.0000	6
2:230760116–230760117	donor_loss	1.0000	4
2:230790865	acceptor_gain	1.0000
2:230790870–230790871	acceptor_loss	1.0000	6
2:230791037–230791038	donor_loss	1.0000	3
2:230798727–230798728	acceptor_loss	1.0000	3
2:230798898–230798899	donor_loss	1.0000	5
2:230810261–230810262	acceptor_loss	1.0000	5
2:230810323–230810324	donor_loss	1.0000	5
2:230814115–230814116	donor_loss	1.0000	5

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

2 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Clear Cell Carcinoma (TCGA)	favorable	2.27e-06
Pancreatic Adenocarcinoma (TCGA)	unfavorable	0.000118

Disease associations

OMIM: gene MIM:612174 | disease phenotypes:

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL2010621 (SINGLE PROTEIN), CHEMBL3885534 (PROTEIN COMPLEX)

PharmGKB: 1 entry (CPIC guideline: no)

Binding affinities (BindingDB)

1 measured of 1 human assays (2 total across all organisms); most potent 1 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
CHEMBL5653589	KD	1440 nM

ChEMBL bioactivities

4 potent at pChembl≥5 of 4 total, top 4 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.11	Kd	7.818	nM	CHEMBL5653589
8.11	ED50	7.818	nM	CHEMBL5653589
6.80	Kd	157.3	nM	CHEMBL3752910
6.80	ED50	157.3	nM	CHEMBL3752910

PubChem BioAssay actives

2 with measured affinity, of 19 total; 2 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
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2147976: Binding affinity to human CAB39 incubated for 45 mins by Kinobead based pull down assay	kd	0.0078	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2147976: Binding affinity to human CAB39 incubated for 45 mins by Kinobead based pull down assay	kd	0.1573	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, increases expression	2
Tobacco Smoke Pollution	affects expression, increases expression	2
dicrotophos	decreases expression	1
geldanamycin	increases expression	1
beta-lapachone	increases expression	1
arsenite	decreases reaction, affects binding	1
sodium arsenite	decreases expression	1
benzo(e)pyrene	decreases methylation	1
K 7174	increases expression	1
abrine	increases expression	1
2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide	decreases reaction, increases expression	1
bisphenol S	affects cotreatment, increases methylation	1
jinfukang	decreases expression	1
Resveratrol	affects cotreatment, increases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Vehicle Emissions	decreases reaction, increases expression	1
Benzo(a)pyrene	affects methylation	1
Calcitriol	increases expression	1
Camptothecin	decreases expression	1
Daunorubicin	decreases expression	1
Doxorubicin	decreases expression	1
Etoposide	decreases expression	1
Ivermectin	decreases expression	1
Methapyrilene	decreases methylation	1
Methyl Methanesulfonate	decreases expression	1
Plant Extracts	affects cotreatment, increases expression	1
Ribonucleotides	affects binding	1
Rotenone	increases expression	1
Smoke	decreases expression	1
Thiram	increases expression	1

ChEMBL screening assays

7 unique, capped per target: 7 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5651018	Binding	Binding affinity to human CAB39 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*

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for CAB39 across ~30M SureChEMBL compounds — explore on Sugi Predict.