CABYR

Summary

CABYR (calcium binding tyrosine phosphorylation regulated, HGNC:15569) is a protein-coding gene on chromosome 18q11.2, encoding Calcium-binding tyrosine phosphorylation-regulated protein (O75952). May function as a regulator of both motility- and head-associated functions such as capacitation and the acrosome reaction.

To reach fertilization competence, spermatozoa undergo a series of morphological and molecular maturational processes, termed capacitation, involving protein tyrosine phosphorylation and increased intracellular calcium. The protein encoded by this gene localizes to the principal piece of the sperm flagellum in association with the fibrous sheath and exhibits calcium-binding when phosphorylated during capacitation. A pseudogene on chromosome 3 has been identified for this gene. Alternatively spliced transcript variants encoding distinct protein isoforms have been found for this gene.

Source: NCBI Gene 26256 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 88 total
• MANE Select transcript: NM_153769

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:15569
Approved symbol	CABYR
Name	calcium binding tyrosine phosphorylation regulated
Location	18q11.2
Locus type	gene with protein product
Status	Approved
Aliases	FSP-2, CBP86, CT88
Ensembl gene	ENSG00000154040
Ensembl biotype	protein_coding
OMIM	612135
Entrez	26256

Gene structure

Transcript identifiers

Ensembl transcripts: 25 — 20 protein_coding, 3 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined

ENST00000327201, ENST00000399481, ENST00000399496, ENST00000399499, ENST00000415309, ENST00000463087, ENST00000486759, ENST00000577705, ENST00000579102, ENST00000579956, ENST00000581397, ENST00000581872, ENST00000582229, ENST00000584752, ENST00000585037, ENST00000621648, ENST00000625720, ENST00000627314, ENST00000631138, ENST00000915916, ENST00000915917, ENST00000915918, ENST00000915919, ENST00000915920, ENST00000953052

RefSeq mRNA: 7 — MANE Select: NM_153769 NM_001308231, NM_012189, NM_138643, NM_138644, NM_153768, NM_153769, NM_153770

CCDS: CCDS11881, CCDS11882, CCDS11883, CCDS42420, CCDS45840, CCDS77166

Canonical transcript exons

ENST00000399496 — 6 exons

Exon	Start	End
ENSE00002238599	24139062	24139118
ENSE00002257716	24143091	24143259
ENSE00002706351	24161516	24161600
ENSE00003470774	24143360	24143413
ENSE00003633818	24155701	24156042
ENSE00003672208	24159472	24160069

Expression profiles

Bgee: expression breadth ubiquitous, 197 present calls, max score 99.92.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 6.2806 / max 816.5539, expressed in 1296 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
169733	4.6145	1090
169731	1.3706	783
169734	0.1269	21
169732	0.1214	29
169735	0.0472	12

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
sperm	CL:0000019	99.92	gold quality
left testis	UBERON:0004533	99.32	gold quality
right testis	UBERON:0004534	99.16	gold quality
male germ cell	CL:0000015	99.04	gold quality
adult organism	UBERON:0007023	97.65	gold quality
testis	UBERON:0000473	96.91	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	90.91	gold quality
cortical plate	UBERON:0005343	90.30	gold quality
oocyte	CL:0000023	90.13	gold quality
right uterine tube	UBERON:0001302	87.69	gold quality
secondary oocyte	CL:0000655	86.84	gold quality
adenohypophysis	UBERON:0002196	84.83	gold quality
pituitary gland	UBERON:0000007	84.39	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	83.90	gold quality
anterior cingulate cortex	UBERON:0009835	83.90	gold quality
cingulate cortex	UBERON:0003027	83.76	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	83.68	gold quality
right frontal lobe	UBERON:0002810	83.65	gold quality
Brodmann (1909) area 9	UBERON:0013540	83.24	gold quality
prefrontal cortex	UBERON:0000451	82.03	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	81.77	gold quality
spinal cord	UBERON:0002240	81.74	gold quality
endocervix	UBERON:0000458	81.70	gold quality
right adrenal gland cortex	UBERON:0035827	80.66	gold quality
neocortex	UBERON:0001950	80.50	gold quality
ganglionic eminence	UBERON:0004023	80.46	gold quality
amygdala	UBERON:0001876	80.01	gold quality
frontal cortex	UBERON:0001870	79.84	gold quality
corpus callosum	UBERON:0002336	79.53	gold quality
right adrenal gland	UBERON:0001233	79.47	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-GEOD-134144	yes	31.84
E-MTAB-9801	yes	6.79
E-ANND-3	no	2.75

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 13)

• sequencing, cloning, expression and characterization (PMID:11820818)
• Northern blot showed that CABYR transcripts were expressed more distinctly in the fetal brain than in the adult brain, suggesting that this protein may play a role during brain development. (PMID:15752768)
• splice variants containing CR-B are expressed during spermiogenesis and assemble into the fibrous sheath of the principal piece; however, calcium binding occurs only to those CABYR isoforms containing CABYR-A (PMID:16139264)
• The expression of NF-kappaB was not significantly affected by silencing CABYR in 293T cells. (PMID:20954286)
• CABYR variants form a complex not only with the scaffolding protein AKAP3 but also with another RII-like domain-containing protein in the sperm fibrous sheath. (PMID:21240291)
• High CABYR is associated with neoplasms. (PMID:21274509)
• CABYR-c is highly expressed in hepatocellular carcinoma tissues and may play an oncogenic role in heptocarcinogenesis as well as its progression. (PMID:22285430)
• Short hairpin RNA-mediated knockdown of CABYR-a/b significantly inhibited the proliferation of NCI-H460 and A549 cells and resulted in the attenuation of Akt phosphorylation, which is constitutively active in lung cancer cells. (PMID:24362251)
• The results demonstrate that depletion of CABYR-a/b sensitizes lung cancer cells to TRAIL-induced apoptosis through YAP/p73-mediated DR5 upregulation. (PMID:26843620)
• Low CABYR expression is associated with colon cancer. (PMID:28121627)
• There is downregulation of both ROPN1 and CABYR in asthenozoospermic samples and importantly, a positive correlation between the expression of the two genes, suggesting that ROPN1 and CABYR co-expression is a prerequisite for normal flagellar function and sperm motility. (PMID:29247344)
• Study of (Co-IP) and reverse co-immunoprecipitation (Co-IP) of CBP86-IV (TSCBP86-IV or CABYR) in human sperm cell lysate identified phosphoglycerate kinase 2 (PGK2) as interacting partner of CABYR. Protein interactions were further confirmed by yeast two-hybrid system. (PMID:30972801)
• Upregulated calcium-binding tyrosine phosphorylation-regulated protein-a/b regulates cell proliferation and apoptosis and predicts poor prognosis in hepatocellular carcinoma. (PMID:31692072)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Cabyr	ENSMUSG00000024430
rattus_norvegicus	Cabyr	ENSRNOG00000047436

Protein

Protein identifiers

Calcium-binding tyrosine phosphorylation-regulated protein — O75952 (reviewed: O75952)

Alternative names: Calcium-binding protein 86, Cancer/testis antigen 88, Fibrousheathin II, Fibrousheathin-2, Testis-specific calcium-binding protein CBP86

All UniProt accessions (9): O75952, A0A024RC21, A0A0D9SFQ2, G9BQT7, J3KRI0, J3KT09, J3KTE8, J3QLW5, J3QQK7

UniProt curated annotations — full annotation on UniProt →

Function. May function as a regulator of both motility- and head-associated functions such as capacitation and the acrosome reaction. Isoform 1 binds calcium in vitro. Isoform 2 and isoform 6 probably bind calcium. Isoform 3 and isoform 5 do not bind calcium in vitro. Isoform 4 probably does not bind calcium.

Subunit / interactions. Interacts with FSCB. Isoform 3 self-associates. Isoform 3 and isoform 5 interact with GSK3B. Isoform 1 does not interact with GSK3B.

Subcellular location. Cytoplasm. Cytoskeleton. Cell projection. Cilium. Flagellum Nucleus. Flagellum.

Tissue specificity. Expressed in elongating spermatids and spermatozoa (at protein level). Isoform 1 is expressed in testis. Isoform 3 and isoform 5 are also expressed in brain, pancreas and numerous brain tumors.

Post-translational modifications. Isoform 1 is phosphorylated on tyrosine residues during in vitro capacitation. Isoform 3 and isoform 5 are phosphorylated by GSK3B in vitro. Dephosphorylation affects its ability to bind calcium.

Miscellaneous. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay.

Isoforms (6)

UniProt ID	Names	Canonical?
O75952-1	1	yes
O75952-2	2, CBP86-VII
O75952-3	3, CBP86-II
O75952-4	4, CBP86-IV
O75952-5	5, CBP86-III
O75952-6	6, CBP86-VI

RefSeq proteins (7): NP_001295160, NP_036321, NP_619584, NP_619585, NP_722452, NP_722453, NP_722454 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003117	cAMP_dep_PK_reg_su_I/II_a/b	Domain
IPR038848	CABYR	Family
IPR047579	DD_CABYR_SP17	Domain

Pfam: PF02197

UniProt features (31 total): splice variant 7, compositionally biased region 6, mutagenesis site 5, region of interest 4, sequence variant 4, modified residue 2, chain 1, domain 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O75952-F1	48.43	0.11

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 (2): 151, 155

Mutagenesis-validated functional residues (5):

Position	Phenotype
146	does not affect phosphorylation.
151	decreases phosphorylation. abolishes phosphorylation; when associated with a-155.
154	does not affect phosphorylation. does not affect phosphorylation; when associated with a-159.
155	decreases phosphorylation and interaction with gsk3b. abolishes phosphorylation and decreases interaction with gsk3b; wh
159	does not affect phosphorylation. does not affect phosphorylation; when associated with a-154.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 108 (showing top): GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP, GOBP_MALE_GAMETE_GENERATION, GOBP_SPERM_CAPACITATION, GOBP_ANATOMICAL_STRUCTURE_MATURATION, KIM_RESPONSE_TO_TSA_AND_DECITABINE_UP, GOBP_CELL_MATURATION, FISCHER_G2_M_CELL_CYCLE, GOBP_CILIUM_MOVEMENT, LIAO_METASTASIS, GOBP_CELLULAR_PROCESS_INVOLVED_IN_REPRODUCTION_IN_MULTICELLULAR_ORGANISM, GNF2_CCNA1, GOBP_DEVELOPMENTAL_PROCESS_INVOLVED_IN_REPRODUCTION, chr18q11, WEBER_METHYLATED_HCP_IN_FIBROBLAST_DN

GO Biological Process (2): epithelial cilium movement involved in extracellular fluid movement (GO:0003351), sperm capacitation (GO:0048240)

GO Molecular Function (6): calcium ion binding (GO:0005509), SH3 domain binding (GO:0017124), enzyme binding (GO:0019899), protein binding (GO:0005515), protein domain specific binding (GO:0019904), metal ion binding (GO:0046872)

GO Cellular Component (12): extracellular region (GO:0005576), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), cytoskeleton (GO:0005856), motile cilium (GO:0031514), sperm fibrous sheath (GO:0035686), sperm principal piece (GO:0097228), sperm end piece (GO:0097229), cilium (GO:0005929), cell projection (GO:0042995)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	8
sperm flagellum	3
protein binding	2
cilium movement	1
extracellular transport	1
microtubule-based transport	1
developmental process involved in reproduction	1
spermatid development	1
cellular process involved in reproduction in multicellular organism	1
cell maturation	1
metal ion binding	1
protein domain specific binding	1
binding	1
cation binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular anatomical structure	1
cytoplasm	1
intracellular membraneless organelle	1
cilium	1
intraciliary transport particle	1
membrane-bounded organelle	1
plasma membrane bounded cell projection	1

Protein interactions and networks

STRING

1425 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CABYR	AKAP3	O75969	962
CABYR	ROPN1	Q9HAT0	953
CABYR	FSCB	Q5H9T9	953
CABYR	SPA17	Q15506	945
CABYR	ROPN1L	Q96C74	917
CABYR	AKAP1	Q92667	793
CABYR	RHPN1	Q8TCX5	761
CABYR	AKAP4	Q5JQC9	738
CABYR	PRKAR2A	P13861	732
CABYR	TSSK4	Q6SA08	618
CABYR	ODF2	Q5BJF6	573
CABYR	TEKT4	Q8WW24	559
CABYR	SPATA6	Q9NWH7	526
CABYR	DNAH1	Q9P2D7	500
CABYR	QRICH1	Q2TAL8	496

IntAct

4 interactions, top by confidence:

A	B	Type	Score
CABYR	DNAJB12	psi-mi:“MI:0915”(physical association)	0.400
GSK3B	CABYR	psi-mi:“MI:0915”(physical association)	0.370
CABYR	htpG	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (10): CABYR (Two-hybrid), CABYR (Reconstituted Complex), CABYR (Biochemical Activity), CABYR (Proximity Label-MS), CABYR (Proximity Label-MS), DNAJB12 (Affinity Capture-MS), CABYR (Affinity Capture-MS), CABYR (Two-hybrid), CABYR (Two-hybrid), CABYR (Affinity Capture-Western)

ESM2 similar proteins: A2ASS6, A8DYP0, E9QMW4, G4SLH0, J7M799, M9MRD1, O15061, O43491, O55103, O70318, O75952, O77788, P07197, P08553, P08855, P11799, P12839, P16053, P27321, P51125, P54938, P57786, P82179, P83741, Q06637, Q13061, Q23551, Q28820, Q4R3X7, Q63425, Q66H38, Q696W0, Q6TS35, Q70IV5, Q7Z589, Q7ZUV7, Q86TC9, Q8BMB0, Q8TC56, Q8WZ42

Diamond homologs: O19021, O62770, O62771, O75952, P00515, P12368, P13861, P36425, Q15506, Q4R3X7, Q62252, Q710D7, Q95230, Q9D424

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
GSK3B	unknown	CABYR	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	80
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

944 predictions. Top by Δscore:

Variant	Effect	Δscore
18:24139177:G:GT	donor_gain	1.0000
18:24143090:GTTGA:G	acceptor_gain	1.0000
18:24143256:AGAGG:A	donor_loss	1.0000
18:24143257:GAGGT:G	donor_loss	1.0000
18:24143258:AGGTT:A	donor_loss	1.0000
18:24143259:GGTT:G	donor_loss	1.0000
18:24143260:G:C	donor_loss	1.0000
18:24143261:T:A	donor_loss	1.0000
18:24143346:ATT:A	acceptor_gain	1.0000
18:24155699:A:AG	acceptor_gain	1.0000
18:24155700:G:GA	acceptor_gain	1.0000
18:24155700:GT:G	acceptor_gain	1.0000
18:24155700:GTA:G	acceptor_gain	1.0000
18:24155700:GTAGA:G	acceptor_gain	1.0000
18:24139089:G:GT	donor_gain	0.9900
18:24139177:G:T	donor_gain	0.9900
18:24139178:G:T	donor_gain	0.9900
18:24143089:A:AG	acceptor_gain	0.9900
18:24143089:AGTT:A	acceptor_gain	0.9900
18:24143090:G:GG	acceptor_gain	0.9900
18:24143090:GTT:G	acceptor_gain	0.9900
18:24143090:GTTG:G	acceptor_gain	0.9900
18:24143248:C:CG	donor_gain	0.9900
18:24143347:T:G	acceptor_gain	0.9900
18:24143348:T:A	acceptor_gain	0.9900
18:24155698:CA:C	acceptor_loss	0.9900
18:24155699:A:AC	acceptor_loss	0.9900
18:24139112:A:T	donor_gain	0.9800
18:24139166:T:TG	donor_gain	0.9800
18:24139190:G:GG	donor_gain	0.9800

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000114657 (18:24142287 C>G), RS1000231151 (18:24142112 G>A,T), RS1000339603 (18:24148777 G>A), RS1000556993 (18:24140481 T>C), RS1000639743 (18:24147796 C>G), RS1000772846 (18:24148592 T>C), RS1000788257 (18:24147338 C>G,T), RS1000816729 (18:24152718 T>C,G), RS1000969058 (18:24157238 G>A), RS1001053344 (18:24158950 T>C), RS1001073523 (18:24147510 T>C), RS1001253109 (18:24150325 T>A,C), RS1001317159 (18:24159228 T>C), RS1001445549 (18:24141631 G>A), RS1001493584 (18:24139049 G>C,T)

Disease associations

OMIM: gene MIM:612135 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST009391_1543	Metabolite levels	1.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0010511	niacinamide measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, increases expression, increases methylation	6
Aflatoxin B1	affects expression, decreases methylation, increases expression	5
sodium arsenite	increases expression, decreases expression	4
Nickel	decreases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Silicon Dioxide	increases expression	2
Valproic Acid	affects expression, decreases methylation	2
p-Chloromercuribenzoic Acid	affects cotreatment, increases expression	2
aristolochic acid I	increases expression	1
methylmercuric chloride	increases expression	1
terbufos	increases methylation	1
sulforaphane	increases expression	1
beta-methylcholine	affects expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression, affects cotreatment	1
dorsomorphin	increases expression, affects cotreatment	1
jinfukang	affects cotreatment, increases expression	1
Air Pollutants	decreases expression	1
Arsenic	increases expression	1
Vehicle Emissions	increases expression, increases abundance	1
Cadmium	decreases expression, increases abundance	1
Cannabidiol	increases expression	1
Cisplatin	increases expression, affects cotreatment	1
Doxorubicin	increases expression	1
Fonofos	increases methylation	1
Estradiol	increases expression	1
Fluorouracil	affects response to substance	1
Hydrogen Peroxide	affects expression	1
Lead	affects splicing	1
Mustard Gas	increases expression	1
Parathion	increases methylation	1

Clinical trials (associated diseases)

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