CREB3

Summary

CREB3 (cAMP responsive element binding protein 3, HGNC:2347) is a protein-coding gene on chromosome 9p13.3, encoding Cyclic AMP-responsive element-binding protein 3 (O43889). Endoplasmic reticulum (ER)-bound sequence-specific transcription factor that directly binds DNA and activates transcription.

This gene encodes a transcription factor that is a member of the leucine zipper family of DNA binding proteins. This protein binds to the cAMP-response element and regulates cell proliferation. The protein interacts with host cell factor C1, which also associates with the herpes simplex virus (HSV) protein VP16 that induces transcription of HSV immediate-early genes. This protein and VP16 both bind to the same site on host cell factor C1. It is thought that the interaction between this protein and host cell factor C1 plays a role in the establishment of latency during HSV infection. This protein also plays a role in leukocyte migration, tumor suppression, and endoplasmic reticulum stress-associated protein degradation. Additional transcript variants have been identified, but their biological validity has not been determined.

Source: NCBI Gene 10488 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 62 total
• MANE Select transcript: NM_006368

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2347
Approved symbol	CREB3
Name	cAMP responsive element binding protein 3
Location	9p13.3
Locus type	gene with protein product
Status	Approved
Aliases	LZIP, Luman, sLZIP
Ensembl gene	ENSG00000107175
Ensembl biotype	protein_coding
OMIM	606443
Entrez	10488

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 4 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000353704, ENST00000486056, ENST00000881110, ENST00000881111, ENST00000931188

RefSeq mRNA: 1 — MANE Select: NM_006368 NM_006368

CCDS: CCDS6588

Canonical transcript exons

ENST00000353704 — 9 exons

Exon	Start	End
ENSE00000833026	35732666	35732901
ENSE00000833027	35736392	35736999
ENSE00001371877	35732996	35733143
ENSE00001385803	35733215	35733282
ENSE00003499950	35733396	35733485
ENSE00003523558	35735306	35735374
ENSE00003579954	35736227	35736311
ENSE00003622401	35735109	35735215
ENSE00003685669	35736048	35736132

Expression profiles

Bgee: expression breadth ubiquitous, 276 present calls, max score 95.62.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 25.4679 / max 426.4639, expressed in 1818 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
96626	12.4667	1799
96627	7.9686	1580
96625	3.3496	1533
96623	0.9401	593
96624	0.7430	436

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
adenohypophysis	UBERON:0002196	95.62	gold quality
popliteal artery	UBERON:0002250	95.45	gold quality
right testis	UBERON:0004534	95.45	gold quality
tibial artery	UBERON:0007610	95.45	gold quality
ascending aorta	UBERON:0001496	95.39	gold quality
thoracic aorta	UBERON:0001515	95.39	gold quality
aorta	UBERON:0000947	95.33	gold quality
left testis	UBERON:0004533	95.26	gold quality
descending thoracic aorta	UBERON:0002345	95.19	gold quality
lower esophagus muscularis layer	UBERON:0035833	95.12	gold quality
lower esophagus	UBERON:0013473	95.09	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	95.08	gold quality
right adrenal gland	UBERON:0001233	95.05	gold quality
left adrenal gland	UBERON:0001234	94.93	gold quality
left adrenal gland cortex	UBERON:0035825	94.86	gold quality
left coronary artery	UBERON:0001626	94.84	gold quality
right coronary artery	UBERON:0001625	94.83	gold quality
right adrenal gland cortex	UBERON:0035827	94.82	gold quality
mucosa of stomach	UBERON:0001199	94.81	gold quality
muscle layer of sigmoid colon	UBERON:0035805	94.73	gold quality
cingulate cortex	UBERON:0003027	94.65	gold quality
right frontal lobe	UBERON:0002810	94.63	gold quality
anterior cingulate cortex	UBERON:0009835	94.61	gold quality
stromal cell of endometrium	CL:0002255	94.53	gold quality
pituitary gland	UBERON:0000007	94.42	gold quality
body of stomach	UBERON:0001161	94.12	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	93.98	gold quality
coronary artery	UBERON:0001621	93.95	gold quality
adrenal cortex	UBERON:0001235	93.88	gold quality
adrenal gland	UBERON:0002369	93.81	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-HCAD-5	yes	436.06
E-MTAB-6142	no	360.80
E-ANND-3	no	0.00

Regulation

Is transcription factor: yes

JASPAR motifs

Motif	Name	Family
MA0638.1	CREB3	CREB-related factors
MA0638.2	CREB3	CREB-related factors

JASPAR matrix evidence (PMIDs): PMID:15845366

miRNA regulators (miRDB)

20 targeting CREB3, 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-4262	100.00	73.26	3931
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-670-5P	99.67	69.94	1565
HSA-MIR-4441	99.49	66.56	3216
HSA-MIR-203A-3P	99.49	70.56	2806
HSA-MIR-542-3P	99.34	67.58	1270
HSA-MIR-4270	99.02	66.26	1987
HSA-MIR-2355-5P	98.83	65.51	1589
HSA-MIR-4520-3P	98.75	66.55	963
HSA-MIR-34B-3P	98.70	67.40	1171
HSA-MIR-6754-5P	98.60	65.54	1627
HSA-MIR-595	98.25	67.44	699
HSA-MIR-7850-5P	98.12	67.28	1111
HSA-MIR-3650	97.88	64.89	693
HSA-MIR-4732-3P	97.15	65.45	881
HSA-MIR-1225-5P	96.76	66.85	417
HSA-MIR-4520-5P	93.54	65.23	140

Literature-anchored findings (GeneRIF, showing 36)

• Data show that Luman is processed by regulated intramembrane proteolysis. The site 1 protease (S1P), a Golgi-resident enzyme, may be involved in the processing of Luman. (PMID:12138176)
• HCF-1 contains an activation domain (HCF-1(AD)) required for maximal transactivation by VP16 and its cellular counterpart LZIP. (PMID:12271126)
• LZIP binds to CCR1 and the interaction between CCR1 and LZIP participates in regulation of Lkn-1-dependent cell migration without affecting the chemotactic activities of other CC chemokines that bind to CCR1. (PMID:15001559)
• the host cell factor-binding transcription factor Luman is inhibited by Zhangfei (PMID:15705566)
• Results report the identification of Herp, a gene involved in ER stress-associated protein degradation (ERAD), as a direct target of Luman. (PMID:16940180)
• LZIP functions as a positive regulator in the NF-kappaB activation pathway that is triggered by Lkn-1 without affecting the transcriptional activation of NF-kappaB induced by other CCR1-dependent chemokines (PMID:17192849)
• factor NF-kappaB plays an important role in regulation of LZIP expression, and LZIP expression regulates the monocyte cell migration induced by Lkn-1 (PMID:17296613)
• Luman/CREB3 recruitment factor inhibits Luman activation of the unfolded protein response (PMID:18391022)
• sLZIP functions as a negative regulator in glucocorticoid-induced transcriptional activation of GR by recruitment and activation of HDACs (PMID:19779205)
• These findings suggest that HDAC3 selectively represses CREB3-mediated transcriptional activation and chemotactic signalling in human metastatic breast cancer cells. (PMID:20473547)
• DC-STAMP interacts with ER-resident transcription factor LUMAN which becomes activated during DC maturation. (PMID:20546900)
• sLZIP-regulated ARF4 expression in response to phorbol 12-myristate 13-acetate is involved in breast cancer cell migration. (PMID:22004728)
• sLZIP plays a critical role in MMP-9 expression and is probably involved in invasion and metastasis of cervical cancer (PMID:22009750)
• GSK3beta was downregulate in all samples and CREB3 did not show a significant decrease or increase in its mRNA expression, but the results were significant in mucoepidermoid carcinoma and salivary duct carcinoma. (PMID:23023215)
• propose that JAB1 is a novel binding partner of Luman, which negatively regulates the activity of Luman by promoting its degradation (PMID:23583719)
• A CREB3-ARF4 signalling cascade may be part of a Golgi stress response set in motion by stimuli compromising Golgi capacity. (PMID:24185178)
• Findings indicate that sLZIP negatively regulates AR transactivation in androgen-dependent PCa cells and functions as a positive regulator in tumor progression of androgen-independent PCa. sLZIP contributes to the malignant phenotype of PCa. (PMID:24441043)
• These results indicate that sLZIP plays a role in expression of c-Jun, and migration and invasion of cervical cancer cells via regulation of MMP-9 transcription. (PMID:24481121)
• human sLZIP plays a critical role in development of atherosclerosis and can be used as a therapeutic target molecule for treatment of atherosclerosis (PMID:25077563)
• INHA gene expression is upregulated by cAMP via CRE in human trophoblasts, and TFAP2 regulates this expression by interacting with CRE. (PMID:25358080)
• The authors found that the CREB3/Herp pathway limited the increase in cytosolic Ca2+ concentration and apoptosis early in poliovirus infection and this may reduce the extent of poliovirus-induced damage to the central nervous system during poliomyelitis. (PMID:27405867)
• The essential parts of the Golgi stress response from the perspective of the organelle autoregulation. The pathways of the mammalian Golgi stress response have been identified, specifically the CREB3 pathway. (PMID:28179603)
• Luman, a ubiquitous, non-canonical unfolded protein response (UPR), is identified as a novel regulator of endoplasmic reticulum stress-induced PRNP expression. (PMID:28205568)
• These findings indicate that LZIP is a novel modulator of APOA4 expression and hepatic lipid metabolism. (PMID:28246167)
• sLZIP is a novel co-repressor of ERalpha, and plays a negative role in ERalpha-mediated cell proliferation in breast cancer (PMID:28662179)
• In summary, the authors show here that hepatitis C virus infection is associated with an upregulation of ARF4, which promotes hepatitis C virus replication. Upon hepatitis C virus infection, CREB3 was redistributed to nucleus and activated ARF4 transcription. (PMID:28840565)
• CREB3 was identified as a transcriptional regulator of upregulated ER-Golgi trafficking genes ARF4, COPB1, and USO1, and silencing of these genes attenuated the metastatic phenotype in vitro and lung colonization in vivo. Modulation of ER-Golgi trafficking plays an important role in metastatic progression. (PMID:29249802)
• Results show that CREB3 is a direct target of miR-203a and is considered an oncogene in osteosarcoma tumors and cell lines. (PMID:30940151)
• Endogenous full-length CREB3 was identified as a novel substrate for ERAD in HEK293 cells. (PMID:31291699)
• Knockdown of CREB3 activates endoplasmic reticulum stress and induces apoptosis in glioblastoma. (PMID:31612863)
• The stability of CREB3/Luman is regulated by protein kinase CK2 phosphorylation. (PMID:31941600)
• Role of small leucine zipper protein in hepatic gluconeogenesis and metabolic disorder. (PMID:33355643)
• Comparative Analysis of CREB3 and CREB3L2 Protein Expression in HEK293 Cells. (PMID:33803345)
• CREB3 Plays an Important Role in HPSE-Facilitated HSV-1 Release in Human Corneal Epithelial Cells. (PMID:35746643)
• Potentially functional genetic variants in ferroptosis-related CREB3 and GALNT14 genes predict survival of hepatitis B virus-related hepatocellular carcinoma. (PMID:38151984)
• Dysregulated CREB3 cleavage at the nuclear membrane induces karyoptosis-mediated cell death. (PMID:38480902)

Cross-species orthologs

9 orthologs

Organism	Symbol	Gene ID
danio_rerio	creb3l3l	ENSDARG00000020926
mus_musculus	Creb3	ENSMUSG00000028466
rattus_norvegicus	Creb3	ENSRNOG00000016452
drosophila_melanogaster	CrebA	FBGN0004396
drosophila_melanogaster	Atf6	FBGN0033010
drosophila_melanogaster	CrebB	FBGN0265784
caenorhabditis_elegans		WBGENE00000222
caenorhabditis_elegans		WBGENE00000793
caenorhabditis_elegans		WBGENE00016162

Paralogs (9): CREB3L3 (ENSG00000060566), CREM (ENSG00000095794), ATF6 (ENSG00000118217), CREB1 (ENSG00000118260), ATF1 (ENSG00000123268), CREB3L4 (ENSG00000143578), CREB3L1 (ENSG00000157613), CREB3L2 (ENSG00000182158), ATF6B (ENSG00000213676)

Protein

Protein identifiers

Cyclic AMP-responsive element-binding protein 3 — O43889 (reviewed: O43889)

Alternative names: Leucine zipper protein, Luman, Transcription factor LZIP-alpha

All UniProt accessions (1): O43889

UniProt curated annotations — full annotation on UniProt →

Function. Endoplasmic reticulum (ER)-bound sequence-specific transcription factor that directly binds DNA and activates transcription. Plays a role in the unfolded protein response (UPR), promoting cell survival versus ER stress-induced apoptotic cell death. Also involved in cell proliferation, migration and differentiation, tumor suppression and inflammatory gene expression. Acts as a positive regulator of LKN-1/CCL15-induced chemotaxis signaling of leukocyte cell migration. Associates with chromatin to the HERPUD1 promoter. Also induces transcriptional activation of chemokine receptors. (Microbial infection) Plays a role in human immunodeficiency virus type 1 (HIV-1) virus protein expression. (Microbial infection) May play a role as a cellular tumor suppressor that is targeted by the hepatitis C virus (HCV) core protein. (Microbial infection) Plays a role in herpes simplex virus-1 (HSV-1) latent infection and reactivation from latency. Represses the VP16-mediated transactivation of immediate early genes of the HSV-1 virus by sequestering host cell factor-1 HCFC1 in the ER membrane of sensory neurons, thereby preventing the initiation of the replicative cascade leading to latent infection. Functions as a negative transcriptional regulator in ligand-induced transcriptional activation of the glucocorticoid receptor NR3C1 by recruiting and activating histone deacetylases (HDAC1, HDAC2 and HDAC6). Also decreases the acetylation level of histone H4. Does not promote the chemotactic activity of leukocyte cells. This is the transcriptionally active form that translocates to the nucleus and activates unfolded protein response (UPR) target genes during endoplasmic reticulum (ER) stress response. Binds the cAMP response element (CRE) (consensus: 5’-GTGACGT[AG][AG]-3’) and C/EBP sequences present in many promoters to activate transcription of the genes. Binds to the unfolded protein response element (UPRE) consensus sequences sites. Binds DNA to the 5’-CCAC[GA]-3’half of ERSE II (5’-ATTGG-N-CCACG-3’). (Microbial infection) Activates transcription of genes required for reactivation of the latent HSV-1 virus. Its transcriptional activity is inhibited by CREBZF in a HCFC1-dependent manner, by the viral transactivator protein VP16. Binds DNA to the cAMP response element (CRE) (consensus: 5’-GTGACGT[AG][AG]-3’) and C/EBP sequences present in many viral promoters. (Microbial infection) Its transcriptional activity is inhibited by CREBZF in a HCFC1-dependent manner, by the viral transactivator HCV core protein.

Subunit / interactions. Homodimer. Isoform 1 interacts with HCFC1; the interaction is required to stimulate CREB3 transcriptional activity. Isoform 1 interacts with CREBZF; the interaction occurs only in combination with HCFC1. Isoform 1 interacts (via central part and transmembrane region) with DCSTAMP (via C-terminus cytoplasmic domain). Isoform 1 interacts with OS9. Isoform 1 interacts (via leucine-zipper domain) with CREBRF (via leucine-zipper domain); the interaction occurs only after CREB3 activation and promotes CREB3 degradation. Isoform 1 interacts (via C-terminal domain) with CCR1. (Microbial infection) Interacts with the HCV core protein; homodimerization is prevented by the HCV core protein. Isoform 1 interacts (via leucine-zipper and transmembrane domains) with HIV-1 TMgp41 (via cytoplasmic domain); the interaction reduces CREB3 stability. Processed cyclic AMP-responsive element-binding protein 3 interacts with HIV-1 Tat.

Subcellular location. Endoplasmic reticulum membrane. Golgi apparatus Cytoplasm Nucleus. Cytoplasm Nucleus.

Tissue specificity. Ubiquitously expressed. Expressed in dendritic cells (DC). Weakly expressed in monocytes (at protein level).

Post-translational modifications. First proteolytically cleaved by site-1 protease (S1P) that generates membrane-associated N-terminus and a luminal C-terminus forms. The membrane-associated N-terminus form is further proteolytically processed probably by the site-2 protease (S2P) through a regulated intramembrane proteolysis (RIP), releasing the transcriptional active processed cyclic AMP-responsive element-binding protein 3 form, which is transported to the nucleus. The proteolytic cleavage is strongly induced during dendritic cell (DC) maturation and inhibited by DCSTAMP. That form is rapidly degraded. N-glycosylated.

Induction. Up-regulated upon differentiation of monocytes towards immature dendritic cells (DC). Down-regulated upon DC maturation. Up-regulated by endoplasmic reticulum stress triggered by thapsigargin (Tg) or tunicamycin (Tm). Up-regulated by CCR1-dependent chemokines in an immediate early response and biphasic manner and by NF-kappa-B.

Miscellaneous. Does not contain a helical transmembrane domain.

Similarity. Belongs to the bZIP family. ATF subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
O43889-2	1, LZIP	yes
O43889-3	2, small LZIP, sLZIP

RefSeq proteins (1): NP_006359* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004827	bZIP	Domain
IPR046347	bZIP_sf	Homologous_superfamily
IPR051381	CREB_ATF_subfamily	Family

Pfam: PF00170

UniProt features (33 total): mutagenesis site 10, sequence conflict 6, short sequence motif 3, region of interest 3, chain 2, site 2, glycosylation site 2, topological domain 2, splice variant 1, transmembrane region 1, domain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O43889-F1	61.35	0.20

Functional residue map

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

Catalytic / active sites (2): 263–264 (cleavage; by ps1); 266–267 (cleavage; by ps1)

Glycosylation sites (2): 307, 348

Mutagenesis-validated functional residues (10):

Position	Phenotype
12–13	does not inhibit interaction with hcfc1. reduces transcriptional activation. inhibits strongly transcriptional activatio
16–17	does not affect the transcriptional activation of the glucocorticoid receptor nr3c1; when associated with 57-a-a-58 (iso
57–58	does not affect the transcriptional activation of the glucocorticoid receptor nr3c1; when associated with 16-a-a-17 (iso
57–58	does not inhibit interaction with hcfc1. reduces transcriptional activation. inhibits strongly transcriptional activatio
78–81	inhibits interaction with hcfc1. reduces transcriptional activation. inhibits strongly transcriptional activation; when
81	does not retain hcfc1 in the cytoplasm, does not interact with hcfc1, does not activate promoter and fail to protect cel
160	does not bind to dna but retains its ability to interact with hcfc1. reduces transcriptional activation of unfolded prot
252	does not inhibit proteolytic cleavage and transcriptional activation.
264	inhibits proteolytic cleavage and transcriptional activation.
267	inhibits proteolytic cleavage and transcriptional activation.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-8874211	CREB3 factors activate genes

MSigDB gene sets: 274 (showing top): GOBP_NEGATIVE_REGULATION_OF_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS, GOBP_POSITIVE_REGULATION_OF_CALCIUM_ION_TRANSPORT, REACTOME_UNFOLDED_PROTEIN_RESPONSE_UPR, GOBP_MYELOID_LEUKOCYTE_MIGRATION, GOBP_CELL_CHEMOTAXIS, GOBP_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS, STARK_PREFRONTAL_CORTEX_22Q11_DELETION_DN, GOBP_GROWTH, GOBP_INDUCTION_OF_POSITIVE_CHEMOTAXIS, TGACCTY_ERR1_Q2, AP2_Q3, GGGTGGRR_PAX4_03, GOBP_REGULATION_OF_POSITIVE_CHEMOTAXIS, GOBP_REGULATION_OF_LEUKOCYTE_MIGRATION, GOBP_CELLULAR_RESPONSE_TO_TOPOLOGICALLY_INCORRECT_PROTEIN

GO Biological Process (20): regulation of cell growth (GO:0001558), DNA-templated transcription (GO:0006351), regulation of transcription by RNA polymerase II (GO:0006357), chemotaxis (GO:0006935), release from viral latency (GO:0019046), positive regulation of cell migration (GO:0030335), endoplasmic reticulum unfolded protein response (GO:0030968), regulation of cell population proliferation (GO:0042127), regulation of apoptotic process (GO:0042981), negative regulation of cell cycle (GO:0045786), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of transcription by RNA polymerase II (GO:0045944), induction of positive chemotaxis (GO:0050930), positive regulation of calcium ion transport (GO:0051928), positive regulation of monocyte chemotaxis (GO:0090026), positive regulation of deacetylase activity (GO:0090045), integrated stress response signaling (GO:0140467), negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway (GO:1902236), regulation of DNA-templated transcription (GO:0006355), response to unfolded protein (GO:0006986)

GO Molecular Function (15): RNA polymerase II transcription regulatory region sequence-specific DNA binding (GO:0000977), RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), transcription coregulator binding (GO:0001221), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), DNA binding (GO:0003677), chromatin binding (GO:0003682), DNA-binding transcription factor activity (GO:0003700), cAMP response element binding protein binding (GO:0008140), CCR1 chemokine receptor binding (GO:0031726), identical protein binding (GO:0042802), protein homodimerization activity (GO:0042803), protein dimerization activity (GO:0046983), sequence-specific double-stranded DNA binding (GO:1990837), protein binding (GO:0005515)

GO Cellular Component (13): Golgi membrane (GO:0000139), chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), Golgi apparatus (GO:0005794), cytosol (GO:0005829), membrane (GO:0016020), nuclear body (GO:0016604), neuronal cell body (GO:0043025), RNA polymerase II transcription regulator complex (GO:0090575)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Unfolded Protein Response (UPR)	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
regulation of DNA-templated transcription	3
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
intracellular membrane-bounded organelle	3
cytoplasm	3
transcription by RNA polymerase II	2
DNA-templated transcription	2
regulation of transcription by RNA polymerase II	2
transcription cis-regulatory region binding	2
binding	2
protein binding	2
endomembrane system	2
cell growth	1
regulation of growth	1
regulation of cellular component organization	1
gene expression	1
RNA biosynthetic process	1
response to chemical	1
taxis	1
viral process	1
latent virus replication	1
cell migration	1
regulation of cell migration	1
positive regulation of cell motility	1
cellular response to unfolded protein	1
response to endoplasmic reticulum stress	1
intracellular signal transduction	1
cell population proliferation	1
regulation of cellular process	1
apoptotic process	1
regulation of programmed cell death	1
cell cycle	1
negative regulation of cellular process	1
regulation of cell cycle	1
positive regulation of RNA biosynthetic process	1
positive regulation of DNA-templated transcription	1
positive regulation of positive chemotaxis	1
calcium ion transport	1
positive regulation of monoatomic ion transport	1
regulation of calcium ion transport	1

Protein interactions and networks

STRING

1460 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CREB3	NR0B2	Q15466	988
CREB3	HCFC1	P51610	928
CREB3	KLHDC2	Q9Y2U9	899
CREB3	CREBZF	Q9NS37	881
CREB3	HCFC2	Q9Y5Z7	868
CREB3	KLHDC1	Q8N7A1	852
CREB3	HDAC3	O15379	784
CREB3	CREBRF	Q8IUR6	756
CREB3	JUN	P05412	738
CREB3	NMI	Q13287	675
CREB3	HIF3A	Q9Y2N7	622
CREB3	POU2F1	P14859	621
CREB3	IFI35	P80217	614
CREB3	POU2F2	P09086	596
CREB3	ATF6	P18850	594

IntAct

204 interactions, top by confidence:

A	B	Type	Score
HCFC1	CREB3	psi-mi:“MI:0915”(physical association)	0.800
CREB3	HCFC1	psi-mi:“MI:0407”(direct interaction)	0.800
CREB3	ALG3	psi-mi:“MI:0915”(physical association)	0.730
ALG3	CREB3	psi-mi:“MI:0915”(physical association)	0.730
CREB3	CREB3L3	psi-mi:“MI:0407”(direct interaction)	0.620
CREB3	DDIT3	psi-mi:“MI:0407”(direct interaction)	0.620
DDIT3	CREB3	psi-mi:“MI:0407”(direct interaction)	0.620
CREB3L3	CREB3	psi-mi:“MI:0407”(direct interaction)	0.620
CREBZF	CREB3	psi-mi:“MI:0407”(direct interaction)	0.620
CREB3	CREB3	psi-mi:“MI:0407”(direct interaction)	0.590
CREB3	CREB3	psi-mi:“MI:0915”(physical association)	0.590
TAF4	CREB3	psi-mi:“MI:0407”(direct interaction)	0.560
CREB3	ITM2B	psi-mi:“MI:0915”(physical association)	0.550
CREB3	TMEM51	psi-mi:“MI:0915”(physical association)	0.550
CREB3	TMEM140	psi-mi:“MI:0915”(physical association)	0.550
CREB3	MARCHF5	psi-mi:“MI:0915”(physical association)	0.550
CREB3	ACSF2	psi-mi:“MI:0915”(physical association)	0.550
CREB3	DNAJC30	psi-mi:“MI:0915”(physical association)	0.550
CREB3	FIS1	psi-mi:“MI:0915”(physical association)	0.550
CREB3	CYBC1	psi-mi:“MI:0915”(physical association)	0.550
CREB3	PTPN9	psi-mi:“MI:0915”(physical association)	0.550
CREB3	TM4SF4	psi-mi:“MI:0915”(physical association)	0.550

BioGRID (305): CREB3 (Affinity Capture-RNA), CREB3 (Affinity Capture-RNA), OGT (Affinity Capture-MS), BNIP1 (Affinity Capture-MS), MYO5A (Affinity Capture-MS), MYO5C (Affinity Capture-MS), HCFC1 (Affinity Capture-MS), HCFC2 (Affinity Capture-MS), TRIM26 (Affinity Capture-MS), DECR1 (Affinity Capture-MS), NPHP3 (Affinity Capture-MS), NLRX1 (Affinity Capture-MS), CREB3L2 (Affinity Capture-MS), AP3B1 (Affinity Capture-MS), UHRF1BP1 (Affinity Capture-MS)

ESM2 similar proteins: A1L224, A2VD01, D3ZLB7, F6VAN0, G3V909, O02761, O35451, O43889, O77628, O88479, O94983, O97930, P01100, P01101, P01102, P0C0N8, P0C0N9, P11939, P12841, P18850, P20389, P38532, Q00613, Q08CW8, Q08DJ8, Q1LYG4, Q3SYZ3, Q502F0, Q56TN0, Q56TT7, Q5FVM5, Q5RCM9, Q5UEM7, Q5UEM8, Q61817, Q64210, Q66HA2, Q68CJ9, Q6QDP7, Q6ZPJ0

Diamond homologs: A1L224, A2VD01, O43889, O44743, P29747, Q08CW8, Q1LYG4, Q3SYZ3, Q4JFH9, Q502F0, Q5FVM5, Q5RCM9, Q5UEM7, Q5UEM8, Q61817, Q66HA2, Q68CJ9, Q6QDP7, Q70SY1, Q8BH52, Q8SQ19, Q8TEY5, Q91XE9, Q96BA8, Q9D2A5, Q9Z125, Q54Y73, G3V909, P18850, O35451, Q99941, F6VAN0, P27699, Q03060, Q03061, Q1LZH5, Q54RZ9

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
CREB3	“up-regulates quantity by expression”	HERPUD1	“transcriptional regulation”
HCFC1	“up-regulates activity”	CREB3	binding
CSNK2A1	“down-regulates quantity by destabilization”	CREB3	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 155 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
integrated stress response signaling	8	42.2×	7e-09
response to endoplasmic reticulum stress	7	8.8×	7e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	47
Likely benign	3
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

2407 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
9:35735338:T:C	L192P	0.993
9:35735156:A:C	K161N	0.989
9:35735156:A:T	K161N	0.989
9:35735137:G:C	R155P	0.986
9:35736065:T:C	L210P	0.986
9:35735149:G:C	R159P	0.985
9:35735141:G:C	R156S	0.984
9:35735141:G:T	R156S	0.984
9:35735206:T:C	L178S	0.983
9:35736245:T:C	C239R	0.983
9:35735175:C:A	R168S	0.982
9:35735172:A:C	S167R	0.979
9:35735174:C:A	S167R	0.979
9:35735174:C:G	S167R	0.979
9:35735359:T:C	L199P	0.977
9:35736053:T:C	L206P	0.977
9:35735176:G:C	R168P	0.976
9:35736074:T:C	L213P	0.975
9:35735125:T:C	L151P	0.974
9:35733428:G:C	E126D	0.972
9:35733428:G:T	E126D	0.972
9:35735322:G:C	A187P	0.969
9:35735146:T:C	I158T	0.968
9:35735328:A:G	N189D	0.968
9:35735308:T:A	V182D	0.966
9:35736228:T:A	V233D	0.966
9:35735155:A:T	K161I	0.964
9:35735183:A:C	K170N	0.964
9:35735183:A:T	K170N	0.964
9:35735341:A:C	Q193P	0.962

dbSNP variants (sampled 300 via entrez): RS1000622693 (9:35730746 T>G), RS1001405847 (9:35734831 G>A,C), RS1001620260 (9:35735611 G>A,T), RS1002578756 (9:35733982 T>G), RS1002799588 (9:35731892 G>A,C,T), RS1003010507 (9:35737102 A>AG), RS1003171943 (9:35732534 A>C,T), RS1003181197 (9:35733238 G>A,C,T), RS1004234207 (9:35731621 C>G,T), RS1005362157 (9:35735779 G>A), RS1005838734 (9:35732804 A>G), RS1006589690 (9:35734119 GCA>G), RS1006761000 (9:35734241 G>A), RS1007331351 (9:35733598 A>G), RS1007352728 (9:35733121 G>A)

Disease associations

OMIM: gene MIM:606443 | disease phenotypes: MIM:614409, MIM:605726, MIM:614373

GenCC curated gene-disease

Mondo (4): hereditary spastic paraplegia 46 (MONDO:0013737), breast ductal adenocarcinoma (MONDO:0005590), autosomal recessive distal spinal muscular atrophy 2 (MONDO:0011585), amyotrophic lateral sclerosis type 16 (MONDO:0013715)

Orphanet (3): Autosomal recessive spastic paraplegia type 46 (Orphanet:320391), Distal hereditary motor neuropathy, Jerash type (Orphanet:139552), Juvenile amyotrophic lateral sclerosis (Orphanet:300605)

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST010703_52	Brain morphology (MOSTest)	1.000000e-08

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004346	neuroimaging measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D018270	Carcinoma, Ductal, Breast	C04.557.470.200.025.232.500; C04.557.470.615.132.500; C04.588.180.390; C17.800.090.500.390
C535715	Spinal muscular atrophy, Jerash type (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases abundance, increases expression	3
Air Pollutants	decreases expression, increases abundance, increases expression	2
Smoke	decreases expression, increases abundance, increases expression	2
Tretinoin	increases expression	2
Valproic Acid	affects expression, increases expression	2
Cyclosporine	increases expression	2
moringin	affects cotreatment, increases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases methylation	1
geraniol	increases expression	1
butyraldehyde	increases expression	1
manganese chloride	increases abundance, increases expression	1
tamibarotene	increases expression	1
perfluorooctane sulfonic acid	increases expression	1
CGP 52608	affects binding, increases reaction	1
monomethylarsonous acid	increases expression	1
K 7174	increases expression	1
abrine	increases expression	1
Arsenic	increases abundance, increases expression	1
Calcitriol	increases expression, affects cotreatment	1
Cannabidiol	affects cotreatment, increases expression	1
Carbamazepine	affects expression	1
Chelating Agents	affects binding, increases expression	1
Copper	affects binding, increases expression	1
Diethylhexyl Phthalate	increases expression	1
Doxorubicin	decreases expression	1
Manganese	increases abundance, increases expression	1
Methotrexate	affects response to substance	1
Phthalic Acids	increases methylation	1
Sarin	decreases expression	1

Cellosaurus cell lines

4 cell lines: 3 embryonic stem cell, 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_A0S3	SEES3-1V human CREB3, clone1	Embryonic stem cell	Male
CVCL_A0S4	SEES3-1V human CREB3, clone2	Embryonic stem cell	Male
CVCL_A0S5	SEES3-1V human CREB3, clone3	Embryonic stem cell	Male
CVCL_AW16	K562 eGFP-CREB3	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT03414970	PHASE3	ACTIVE_NOT_RECRUITING	Hypofractionated Radiation Therapy After Mastectomy in Preventing Recurrence in Patients With Stage IIa-IIIa Breast Cancer
NCT00461344	PHASE2	TERMINATED	Docetaxel + Doxorubicin as Neoadjuvant Chemotherapy in Patients With Breast Cancer
NCT07499999	PHASE2	NOT_YET_RECRUITING	Randomized Double-Blind Phase II Trial of Baby Exemestane Versus Baby Tamoxifen in Post-Menopausal Women at High Risk for Breast Cancer
NCT00637364	PHASE1/PHASE2	SUSPENDED	High Intensity Focused Ultrasound Tumor Treatment for Pancreatic Cancer Pain
NCT02779855	PHASE1/PHASE2	COMPLETED	Talimogene Laherparepvec in Combination With Neoadjuvant Chemotherapy in Triple Negative Breast Cancer
NCT01753908	EARLY_PHASE1	COMPLETED	Broccoli Sprout Extract in Treating Patients With Breast Cancer
NCT01796041	EARLY_PHASE1	COMPLETED	Intraoperative Imaging of Breast Cancer With Indocyanine Green
NCT01208974	Not specified	ACTIVE_NOT_RECRUITING	Nipple-Areola Complex (NAC) Irradiation After Nipple-Sparing Mastectomy and Reconstruction
NCT01875198	Not specified	TERMINATED	Oncologic Impact of Splenectomy-omitting Radical Pancreatectomy in Well-selected Left-sided Pancreatic Cancer
NCT03543397	Not specified	UNKNOWN	MRI in Ductal Carcinoma in Situ (DCIS)
NCT03834532	Not specified	COMPLETED	Living Well After Breast Surgery