APBB1

Summary

APBB1 (amyloid beta precursor protein binding family B member 1, HGNC:581) is a protein-coding gene on chromosome 11p15.4, encoding Amyloid beta precursor protein binding family B member 1 (O00213). Transcription coregulator that can have both coactivator and corepressor functions.

The protein encoded by this gene is a member of the Fe65 protein family. It is an adaptor protein localized in the nucleus. It interacts with the Alzheimer’s disease amyloid precursor protein (APP), transcription factor CP2/LSF/LBP1 and the low-density lipoprotein receptor-related protein. APP functions as a cytosolic anchoring site that can prevent the gene product’s nuclear translocation. This encoded protein could play an important role in the pathogenesis of Alzheimer’s disease. It is thought to regulate transcription. Also it is observed to block cell cycle progression by downregulating thymidylate synthase expression. Multiple alternatively spliced transcript variants encoding different isoforms have been described for this gene.

Source: NCBI Gene 322 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 117 total — 3 pathogenic
• MANE Select transcript: NM_001164

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:581
Approved symbol	APBB1
Name	amyloid beta precursor protein binding family B member 1
Location	11p15.4
Locus type	gene with protein product
Status	Approved
Aliases	Fe65
Ensembl gene	ENSG00000166313
Ensembl biotype	protein_coding
OMIM	602709
Entrez	322

Gene structure

Transcript identifiers

Ensembl transcripts: 31 — 23 protein_coding, 6 retained_intron, 1 protein_coding_CDS_not_defined, 1 non_stop_decay

ENST00000299402, ENST00000311051, ENST00000524626, ENST00000526240, ENST00000526925, ENST00000529519, ENST00000529778, ENST00000529890, ENST00000530885, ENST00000532020, ENST00000533139, ENST00000533407, ENST00000534188, ENST00000608394, ENST00000608435, ENST00000608645, ENST00000608655, ENST00000608704, ENST00000609331, ENST00000609360, ENST00000905158, ENST00000905159, ENST00000905160, ENST00000905161, ENST00000905162, ENST00000946523, ENST00000946524, ENST00000946525, ENST00000946526, ENST00000946527, ENST00000946528

RefSeq mRNA: 8 — MANE Select: NM_001164 NM_001164, NM_001257319, NM_001257320, NM_001257321, NM_001257323, NM_001257325, NM_001257326, NM_145689

CCDS: CCDS31410, CCDS58114, CCDS66015, CCDS66016, CCDS66017, CCDS66018

Canonical transcript exons

ENST00000609360 — 15 exons

Exon	Start	End
ENSE00001291677	6410627	6411361
ENSE00003594867	6395125	6395701
ENSE00003603704	6403647	6403822
ENSE00003703563	6402576	6402725
ENSE00003704523	6402082	6402209
ENSE00003704598	6403145	6403208
ENSE00003706617	6401977	6401982
ENSE00003707556	6403488	6403544
ENSE00003707989	6396100	6396215
ENSE00003708202	6401345	6401429
ENSE00003708559	6401574	6401688
ENSE00003708686	6400989	6401072
ENSE00003710669	6395786	6395962
ENSE00003786712	6403319	6403404
ENSE00003843787	6418985	6419094

Expression profiles

Bgee: expression breadth ubiquitous, 242 present calls, max score 99.39.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 15.4628 / max 312.5537, expressed in 1432 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
118417	12.6285	1381
118419	1.1092	657
118418	0.8542	356
118415	0.6222	132
118414	0.1084	60
118413	0.0591	38
118412	0.0427	26
118411	0.0385	10

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right hemisphere of cerebellum	UBERON:0014890	99.39	gold quality
cerebellar hemisphere	UBERON:0002245	99.31	gold quality
cerebellar cortex	UBERON:0002129	99.25	gold quality
right frontal lobe	UBERON:0002810	99.16	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	98.85	gold quality
cortical plate	UBERON:0005343	98.50	gold quality
ganglionic eminence	UBERON:0004023	98.13	gold quality
cerebellum	UBERON:0002037	98.04	gold quality
prefrontal cortex	UBERON:0000451	97.98	gold quality
adenohypophysis	UBERON:0002196	97.67	gold quality
cingulate cortex	UBERON:0003027	97.63	gold quality
Brodmann (1909) area 9	UBERON:0013540	97.62	gold quality
anterior cingulate cortex	UBERON:0009835	97.53	gold quality
amygdala	UBERON:0001876	97.39	gold quality
ventricular zone	UBERON:0003053	97.32	gold quality
apex of heart	UBERON:0002098	97.20	gold quality
nucleus accumbens	UBERON:0001882	97.18	gold quality
spinal cord	UBERON:0002240	97.07	gold quality
pituitary gland	UBERON:0000007	96.43	gold quality
lower esophagus muscularis layer	UBERON:0035833	96.34	gold quality
caudate nucleus	UBERON:0001873	96.30	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	96.30	gold quality
lower esophagus	UBERON:0013473	96.29	gold quality
body of uterus	UBERON:0009853	96.24	gold quality
putamen	UBERON:0001874	96.13	gold quality
mucosa of stomach	UBERON:0001199	95.80	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	95.79	gold quality
neocortex	UBERON:0001950	95.67	gold quality
left ovary	UBERON:0002119	95.49	gold quality
frontal cortex	UBERON:0001870	95.45	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.41

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

2 targets.

Target	Regulation
CLU	Repression
GMPS	Repression

Upstream regulators (CollecTRI, top): GLI3, PURA, SP1, YY1

miRNA regulators (miRDB)

30 targeting APBB1, 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-6797-5P	99.61	66.55	2084
HSA-MIR-1249-5P	99.61	66.55	2049
HSA-MIR-199A-5P	99.51	69.71	1107
HSA-MIR-199B-5P	99.51	69.74	1098
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-1324	99.46	66.57	1302
HSA-MIR-7515	99.31	68.22	1795
HSA-MIR-3606-5P	99.31	69.67	1168
HSA-MIR-4641	99.28	66.64	744
HSA-MIR-3176	99.25	64.35	954
HSA-MIR-3922-3P	99.25	64.96	1136
HSA-MIR-4292	99.16	65.57	1767
HSA-MIR-6791-5P	99.16	65.92	1844
HSA-MIR-4763-3P	99.10	67.83	2649
HSA-MIR-4326	98.97	67.63	962
HSA-MIR-423-5P	98.69	67.48	1522
HSA-MIR-210-5P	98.57	64.37	832
HSA-MIR-3184-5P	98.56	67.13	1491
HSA-MIR-7114-3P	98.42	66.53	569
HSA-MIR-6864-5P	98.38	66.59	1079
HSA-MIR-499B-5P	98.35	68.39	988
HSA-MIR-3689A-5P	98.35	70.12	1049
HSA-MIR-3689B-5P	98.35	70.12	1049
HSA-MIR-3689E	98.35	70.12	1049
HSA-MIR-3689F	98.35	70.08	1052
HSA-MIR-660-3P	98.14	66.04	1434
HSA-MIR-3665	97.73	65.08	975
HSA-MIR-144-5P	97.66	69.90	531
HSA-MIR-665	97.60	65.64	1781
HSA-MIR-921	97.09	66.45	562

Literature-anchored findings (GeneRIF, showing 40)

• The transcriptional activity of the APP intracellular domain-Fe65 complex is inhibited by activation of the NF-kappaB pathway. (PMID:12653567)
• Adjusting for age and sex, we found a slight risk associated with the deletion in intron 13 of the APBB1 gene for subjects less than 65 years. (PMID:12727304)
• gamma-Secretase cleavage and binding to FE65 regulate the nuclear translocation of the intracellular C-terminal domain (ICD) of the APP family of proteins. (PMID:12779321)
• APP and Fe65 mediate transactivation with low density lipoprotein receptor-related protein (PMID:12888553)
• Abnormal accumulations of the amyloid-beta precursor protein associated with the aging cellular muscle fibers and appear to be the key pathogenic event in iclusion-body myositis. (PMID:14569203)
• Alcadein and amyloid beta-protein precursor regulates FE65-dependent gene transactivation (PMID:15037614)
• Fe65 is activated by the APP intracellular domain during transcriptional transactivation (PMID:15044485)
• p65FE65 may be an intracellular mediator in a signaling cascade regulating alpha-secretion of APP (PMID:15647266)
• The present work provides evidence that FE65 plays a role in the regulation of amyloid precursor protein processing in an in vivo transgenic mouse model. (PMID:15816856)
• multiple interactions of AICD with FE65 and 14-3-3gamma modulate FE65-dependent gene transactivation (PMID:16223726)
• FE65 is the key agent of Gal4DB-mediated transcriptional transactivation, whereas Tip60 is an FE65-associated repressor. (PMID:16332686)
• Notch1 intracellular domain plays the role of a negative regulator in AICD signaling via the disruption of the AICD-Fe65-Tip60 trimeric complex. (PMID:17368826)
• Nek6 binds to Fe65 through its (267)PPLP(270) motif; the protein-protein interaction between Nek6 and Fe65 regulates their subcellular localization and cell apoptosis (PMID:17512906)
• We demonstrated that treatment with EGCG reduced the A beta levels by enhancing endogenous APP nonamyloidogenic proteolytic processing. (PMID:17590240)
• Results describe the crystal structures of the human FE65 WW domain (residues 253-289) in the apo form and bound to the peptides PPPPPPLPP and PPPPPPPPPL, which correspond to human Mena residues 313-321 and 347-356, respectively. (PMID:17686488)
• Fe65 regulation of APP proteolysis may be integrally associated with its nuclear signaling function, as all antecedent proteolytic steps prior to release of Fe65 from the membrane are fostered by the APP-Fe65 interaction (PMID:17855370)
• APP-regulated FE65 plays an important role in the early stress response of cells and that FE65 deregulated from APP induces apoptosis. (PMID:18468999)
• Thyroid cancers are characterized by APP upregulation, increased membrane targeting of the APP ectodomain and significantly increased mRNA levels of the APP scaffold proteins JIP1, ShcA and Fe65. (PMID:18480379)
• crystallographic analysis of the human Fe65-phosphotyrosine domain (PMID:18550529)
• Single nucleotide polymorphisms in APBB1 gene is associated with nicotine dependence. (PMID:18777128)
• the beta-sheet edge in some natively folded amyloid oligomers is designed positively to prevent beta aggregation (PMID:18800165)
• Study determined the crystal structure of the carboxy-terminal APP intracellular domain in complex with the C-terminal phosphotyrosine-binding (PTB) domain of Fe65; The unique interface involves the NPxY PTB-binding motif and two alpha helices. (PMID:18833287)
• Dexras1 functions as a suppressor of FE65-APP-mediated transcription, and FE65 tyrosine 547 phosphorylation enhances FE65-APP-mediated transcription, at least in part, by modulating the interaction between FE65 and Dexras1 (PMID:18922798)
• The protein-protein interaction between the WW domain of Fe65 and the putative binding motif of Nedd4-2 down-regulates Fe65 protein stability and subcellular localization through its ubiquitylation, to contribute to cell apoptosis. (PMID:19381069)
• reduced levels of Sp1 resulted in downregulation of endogenous FE65 mRNA and protein (PMID:20091743)
• Both amyloid-beta precursor protein and Fe65 are co-localized in model Hirano bodies associated with Alzheimer’s disease. (PMID:20133016)
• The data of this demonstrated that the induction of AICD/Fe65 or transgelin significantly alters actin dynamics and mitochondrial function in neuronal cells (PMID:20405578)
• Fe65 and Dab1 compete for binding to APP. Dab1 significantly decreased the amount of APP bound to LRP and the level of secreted APP and APP-CTF in LRP expressing cells (PMID:20568118)
• Fe65 binds preferentially to low-density lipoprotein receptor-related protein (LRP) carboxyl terminus when phosphorylated at tyrosine-4507 and in complex with amyloid precursor protein (APP). (PMID:21650223)
• A novel FE65 isoform and the regulation of the splicing events leading to its production may contribute to elucidating neuronal specific roles of FE65 and its contribution to Alzheimer’s disease pathology. (PMID:21824145)
• Phosphorylation of LRP1 regulates the interaction with Fe65. (PMID:21968187)
• Fe65 carries out different functions depending on its location in the regulation of Notch1 signaling. (PMID:22199353)
• A ternary complex consisting of AICD, FE65, and TIP60 down-regulates Stathmin1. (PMID:22902274)
• FE65 interactions with BLM and MCM proteins may contribute to the neuronal cell cycle re-entry observed in brains affected by Alzheimer’s disease. (PMID:23572515)
• The SV2A/FE65 interaction might play a role in synaptic signal transduction. (PMID:24284412)
• Data indicate that Fe65 is a positive estrogen receptor alpha (ERalpha) transcriptional regulator. (PMID:24619425)
• A novel phosphorylation site was identified within Fe65 which mediates gene transcription. (PMID:25397632)
• Targeted enhancement of the signaling through the Fe65-cortactin pathway, by either HDAC6 inhibition or Tip60 activation, may lead to the development of new therapeutic drugs that are effective for patients with metastatic breast cancers. (PMID:26166158)
• FE65 influences APP degradation via the proteasome, and phosphorylation of FE65 Ser(610) by SGK1 regulates binding of FE65 to APP, APP turnover and processing. (PMID:26188042)
• Jagged1 is a novel binding partner of Fe65, and Fe65 may act as a novel effector of Jagged1 signaling. (PMID:26276215)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	apbb1	ENSDARG00000076560
mus_musculus	Apbb1	ENSMUSG00000037032
rattus_norvegicus	Apbb1	ENSRNOG00000018020
caenorhabditis_elegans		WBGENE00001410

Paralogs (2): APBB3 (ENSG00000113108), APBB2 (ENSG00000163697)

Protein

Protein identifiers

Amyloid beta precursor protein binding family B member 1 — O00213 (reviewed: O00213)

Alternative names: Amyloid-beta A4 precursor protein-binding family B member 1, Protein Fe65

All UniProt accessions (5): A0A075B7G8, O00213, V9GY97, V9GYD5, V9GYR7

UniProt curated annotations — full annotation on UniProt →

Function. Transcription coregulator that can have both coactivator and corepressor functions. Adapter protein that forms a transcriptionally active complex with the gamma-secretase-derived amyloid precursor protein (APP) intracellular domain. Plays a central role in the response to DNA damage by translocating to the nucleus and inducing apoptosis. May act by specifically recognizing and binding histone H2AX phosphorylated on ‘Tyr-142’ (H2AXY142ph) at double-strand breaks (DSBs), recruiting other pro-apoptosis factors such as MAPK8/JNK1. Required for histone H4 acetylation at double-strand breaks (DSBs). Its ability to specifically bind modified histones and chromatin modifying enzymes such as KAT5/TIP60, probably explains its transcription activation activity. Functions in association with TSHZ3, SET and HDAC factors as a transcriptional repressor, that inhibits the expression of CASP4. Associates with chromatin in a region surrounding the CASP4 transcriptional start site(s). Involved in hippocampal neurite branching and neuromuscular junction formation, as a result plays a role in spatial memory functioning. Plays a role in the maintenance of lens transparency. May play a role in muscle cell strength. Acts as a molecular adapter that functions in neurite outgrowth by activating the RAC1-ARF6 axis upon insulin treatment.

Subunit / interactions. Component of a complex, at least composed of APBB1, RASD1/DEXRAS1 and APP. Interacts (via PID domain 2) with APP (with the intracellular domain of the amyloid-beta precursor protein). Interacts (via PID domain 2) with RASD1/DEXRAS1; impairs the transcription activation activity. Interacts (via PID domain 1) with KAT5/TIP60. Interacts (via the WW domain) with the proline-rich region of APBB1IP. Interacts with TSHZ1 and TSHZ2. Interacts (via the WW domain) with histone H2AX (when phosphorylated on ‘Tyr-142’) and the proline-rich region of ENAH. Interacts with MAPK8. Interacts (via PID domain 1) with TSHZ3 (via homeobox domain). Interacts with SET. Found in a trimeric complex with HDAC1 and TSHZ3; the interaction between HDAC1 and APBB1 is mediated by TSHZ3. Interacts (via WWW domain) with NEK6. Interacts (via WWW domain) with ABL1. Interacts with RNF157. Interacts with ARF6.

Subcellular location. Cell membrane. Cytoplasm. Nucleus. Cell projection. Growth cone. Nucleus speckle.

Tissue specificity. Highly expressed in brain; strongly reduced in post-mortem elderly subjects with Alzheimer disease. Expressed preferentially in the brain.

Post-translational modifications. Phosphorylation at Ser-610 by SGK1 promotes its localization to the nucleus. Phosphorylated following nuclear translocation. Phosphorylation at Tyr-547 by ABL1 enhances transcriptional activation activity and reduces the affinity for RASD1/DEXRAS1. Phosphorylated at Ser-459 by PKC upon insulin activation. Acetylation at Lys-204 and Lys-701 by KAT5 promotes its transcription activator activity. Polyubiquitination by RNF157 leads to degradation by the proteasome.

Isoforms (6)

UniProt ID	Names	Canonical?
O00213-1	1	yes
O00213-2	2
O00213-3	3
O00213-4	4, p60Fe65
O00213-5	5
O00213-6	6

RefSeq proteins (8): NP_001155, NP_001244248, NP_001244249, NP_001244250, NP_001244252, NP_001244254, NP_001244255, NP_663722 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001202	WW_dom	Domain
IPR006020	PTB/PI_dom	Domain
IPR011993	PH-like_dom_sf	Homologous_superfamily
IPR036020	WW_dom_sf	Homologous_superfamily
IPR039576	APBB1/2/3	Family

Pfam: PF00397, PF00640

UniProt features (74 total): strand 18, mutagenesis site 16, helix 8, modified residue 6, splice variant 5, turn 5, compositionally biased region 4, region of interest 4, domain 3, sequence variant 2, sequence conflict 2, chain 1

Structure

Experimental structures (PDB)

11 structures.

PDB	Method	Resolution (Å)
2HO2	X-RAY DIFFRACTION	1.33
2OEI	X-RAY DIFFRACTION	1.35
3DXE	X-RAY DIFFRACTION	2
3DXC	X-RAY DIFFRACTION	2.1
3D8D	X-RAY DIFFRACTION	2.2
3DXD	X-RAY DIFFRACTION	2.2
2IDH	X-RAY DIFFRACTION	2.28
5NQH	X-RAY DIFFRACTION	2.6
3D8F	X-RAY DIFFRACTION	2.7
3D8E	X-RAY DIFFRACTION	2.8
2E45	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O00213-F1	60.75	0.30

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 (6): 204, 459, 517, 547, 610, 701

Mutagenesis-validated functional residues (16):

Position	Phenotype
117	no effect on phosphorylation by abl1.
204	mimics acetylation; leading to increased transcription activator activity; when associated with q-701.
204	abolished acetylation by kat5, leading to decreased transcription activator activity; when associated with r-701.
234	no effect on phosphorylation by abl1.
269–271	impairs transcriptional activation and inhibits binding to abl1.
269	no effect on phosphorylation by abl1.
270	no effect on phosphorylation by abl1.
403	no effect on phosphorylation by abl1.
459	loss of pkc-mediated phosphorylation.
459	increased activation of the rac1-arf6 axis.
467	no effect on phosphorylation by abl1.
546	no effect on phosphorylation by abl1.
547	abrogates phosphorylation and stimulation of transcription by abl1, and increases the interaction with rasd1/dexras1.
658	no effect on phosphorylation by abl1.
701	mimics acetylation; leading to increased transcription activator activity; when associated with q-204.
701	abolished acetylation by kat5, leading to decreased transcription activator activity; when associated with r-204.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-5693565	Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks
R-HSA-5693532	DNA Double-Strand Break Repair
R-HSA-5693606	DNA Double Strand Break Response
R-HSA-73894	DNA Repair

MSigDB gene sets: 202 (showing top): MODY_HIPPOCAMPUS_POSTNATAL, GOBP_CELL_CYCLE_PHASE_TRANSITION, MAZ_Q6, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, GOBP_POSITIVE_REGULATION_OF_PROTEIN_LOCALIZATION, GOBP_NEUROGENESIS, YY1_Q6, MODULE_66, GOBP_REGULATION_OF_PROTEIN_SECRETION, GOBP_REGULATION_OF_CELL_PROJECTION_ORGANIZATION, GOBP_NEGATIVE_REGULATION_OF_CELL_CYCLE_PROCESS, GOBP_MUSCLE_CONTRACTION, GOBP_NEGATIVE_REGULATION_OF_CELL_CYCLE, GOBP_REGULATION_OF_CELL_CYCLE

GO Biological Process (14): negative regulation of transcription by RNA polymerase II (GO:0000122), chromatin organization (GO:0006325), regulation of DNA-templated transcription (GO:0006355), apoptotic process (GO:0006915), smooth muscle contraction (GO:0006939), DNA damage response (GO:0006974), signal transduction (GO:0007165), axonogenesis (GO:0007409), positive regulation of neuron projection development (GO:0010976), positive regulation of apoptotic process (GO:0043065), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of transcription by RNA polymerase II (GO:0045944), positive regulation of protein secretion (GO:0050714), negative regulation of cell cycle G1/S phase transition (GO:1902807)

GO Molecular Function (9): amyloid-beta binding (GO:0001540), chromatin binding (GO:0003682), transcription coactivator activity (GO:0003713), ubiquitin protein ligase binding (GO:0031625), histone binding (GO:0042393), low-density lipoprotein particle receptor binding (GO:0050750), molecular adaptor activity (GO:0060090), proline-rich region binding (GO:0070064), protein binding (GO:0005515)

GO Cellular Component (11): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), endoplasmic reticulum (GO:0005783), plasma membrane (GO:0005886), nuclear speck (GO:0016607), lamellipodium (GO:0030027), growth cone (GO:0030426), synapse (GO:0045202), membrane (GO:0016020), cell projection (GO:0042995)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
DNA Double Strand Break Response	1
DNA Repair	1
DNA Double-Strand Break Repair	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
binding	3
regulation of transcription by RNA polymerase II	2
transcription by RNA polymerase II	2
DNA-templated transcription	2
positive regulation of DNA-templated transcription	2
protein binding	2
intracellular membrane-bounded organelle	2
negative regulation of DNA-templated transcription	1
cellular component organization	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
muscle contraction	1
cellular response to stress	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
cell morphogenesis involved in neuron differentiation	1
neuron projection morphogenesis	1
axon development	1
regulation of neuron projection development	1
neuron projection development	1
positive regulation of cell projection organization	1
apoptotic process	1
regulation of apoptotic process	1
positive regulation of programmed cell death	1
regulation of DNA-templated transcription	1
positive regulation of RNA biosynthetic process	1
protein secretion	1
regulation of protein secretion	1
positive regulation of protein transport	1
positive regulation of secretion by cell	1
cell cycle G1/S phase transition	1
negative regulation of cell cycle phase transition	1
regulation of cell cycle G1/S phase transition	1

Protein interactions and networks

STRING

2440 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
APBB1	APP	P05067	998
APBB1	KAT5	Q92993	998
APBB1	APLP2	Q06481	926
APBB1	APLP1	P51693	925
APBB1	TFCP2	Q12800	904
APBB1	LRP8	Q14114	862
APBB1	APBB1IP	Q7Z5R6	820
APBB1	APBA1	Q02410	809
APBB1	APBA2	Q99767	785
APBB1	SPON1	Q9HCB6	781
APBB1	BACE1	P56817	774
APBB1	CD82	P27701	764
APBB1	LRP1	Q07954	754
APBB1	MAPK8IP1	Q9UQF2	723
APBB1	PTBP1	P26599	715

IntAct

88 interactions, top by confidence:

A	B	Type	Score
APP	APBB1	psi-mi:“MI:0915”(physical association)	0.910
APBB1	APP	psi-mi:“MI:0915”(physical association)	0.910
APP	APBB1	psi-mi:“MI:0914”(association)	0.910
APP	APBB1	psi-mi:“MI:0915”(physical association)	0.740
APP	APBB1	psi-mi:“MI:0914”(association)	0.740
APBB1	APP	psi-mi:“MI:0407”(direct interaction)	0.740
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
APBB1	LRP1	psi-mi:“MI:0407”(direct interaction)	0.700
LRP1	APBB1	psi-mi:“MI:0915”(physical association)	0.700
APBB1	ARF6	psi-mi:“MI:0915”(physical association)	0.630
ARF6	APBB1	psi-mi:“MI:0915”(physical association)	0.630
APBB1	ARF6	psi-mi:“MI:0407”(direct interaction)	0.630
APBB1	Sv2a	psi-mi:“MI:0915”(physical association)	0.560
APBB1	Sv2a	psi-mi:“MI:0403”(colocalization)	0.560
APLP2	APBB1	psi-mi:“MI:0915”(physical association)	0.550
CEP104	CCDC66	psi-mi:“MI:2364”(proximity)	0.540
RPN1	APBB1	psi-mi:“MI:0914”(association)	0.530

BioGRID (298): APBB1 (Two-hybrid), APBB1 (Affinity Capture-Western), Rnf157 (Affinity Capture-Western), APBB1 (Affinity Capture-Western), SART3 (Affinity Capture-Western), KAT5 (Affinity Capture-Western), MGRN1 (Affinity Capture-Western), APP (Affinity Capture-Western), APBB1 (Affinity Capture-MS), APBB1 (Affinity Capture-MS), APBB1 (Affinity Capture-MS), APBB1 (Affinity Capture-MS), APBB1 (Affinity Capture-MS), APBB1 (Proximity Label-MS), APBB1 (Proximity Label-MS)

ESM2 similar proteins: A2AKB4, A2APT9, A5PK16, A6H7I3, A6NNM8, A6QLD5, A9Z1V5, B2RYM0, C0HAC0, D2H8V8, O00213, O15040, P46933, P59644, Q13615, Q1L981, Q2YDQ5, Q400C9, Q400G9, Q49LS3, Q4KLY6, Q501R9, Q5PQT2, Q5RA67, Q5RC94, Q5RGT6, Q5SYB0, Q5TIE3, Q5VTE6, Q60943, Q60953, Q69ZM6, Q6P9J5, Q6UX68, Q6ZW76, Q810L3, Q8BLK9, Q8BVF9, Q8K1C0, Q8K296

Diamond homologs: O00213, O35827, O95704, P46933, Q8R1C9, Q92870, Q9BKZ9, Q9DBR4, Q9QXJ1, E9Q5F9, Q9BYW2

SIGNOR signaling

14 interactions.

A	Effect	B	Mechanism
MAPK1	unknown	APBB1	phosphorylation
MAPK3	unknown	APBB1	phosphorylation
ABL1	up-regulates	APBB1	phosphorylation
APBB1	“up-regulates activity”	TSHZ3	relocalization
Gbeta	unknown	APBB1	phosphorylation
ERK1/2	unknown	APBB1	phosphorylation
SGK1	“down-regulates activity”	APBB1	phosphorylation
GSK3B	“up-regulates quantity”	APBB1	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 61 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Signaling by ERBB2 ECD mutants	5	90.8×	5e-07
GRB2 events in ERBB2 signaling	5	85.7×	5e-07
PD-L1(CD274) glycosylation and translocation to plasma membrane	5	70.2×	1e-06
SHC1 events in ERBB2 signaling	5	64.3×	1e-06
Signaling by ERBB2 TMD/JMD mutants	5	64.3×	1e-06
Signaling by ERBB2 KD Mutants	5	57.2×	1e-06
Maturation of spike protein	5	35.9×	8e-06
Maturation of DENV proteins	5	28.6×	2e-05

GO biological processes:

GO term	Partners	Fold	FDR
protein N-linked glycosylation	5	26.3×	3e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	0
Uncertain significance	82
Likely benign	9
Benign	5

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
147641	GRCh38/hg38 11p15.4(chr11:6261582-6637999)x3	Pathogenic
2503522	GRCh37/hg19 11p15.5-15.4(chr11:230615-8821443)x3	Pathogenic
2980	NM_000543.5(SMPD1):c.1493G>T (p.Arg498Leu)	Pathogenic

SpliceAI

2286 predictions. Top by Δscore:

Variant	Effect	Δscore
11:6395959:CTGT:C	acceptor_gain	1.0000
11:6395960:TGTCT:T	acceptor_loss	1.0000
11:6395961:GTCTG:G	acceptor_loss	1.0000
11:6395963:C:CC	acceptor_gain	1.0000
11:6395964:T:G	acceptor_loss	1.0000
11:6400988:CCAA:C	donor_gain	1.0000
11:6401013:T:A	donor_gain	1.0000
11:6401069:TCCA:T	acceptor_gain	1.0000
11:6401070:CCA:C	acceptor_gain	1.0000
11:6401070:CCAC:C	acceptor_gain	1.0000
11:6401071:CA:C	acceptor_gain	1.0000
11:6401071:CAC:C	acceptor_gain	1.0000
11:6401073:C:CC	acceptor_gain	1.0000
11:6401340:CTGA:C	donor_loss	1.0000
11:6401341:TGA:T	donor_loss	1.0000
11:6401342:GA:G	donor_loss	1.0000
11:6401343:A:C	donor_loss	1.0000
11:6401426:TGAT:T	acceptor_gain	1.0000
11:6401427:GATCT:G	acceptor_loss	1.0000
11:6401428:ATCTG:A	acceptor_loss	1.0000
11:6401429:TC:T	acceptor_loss	1.0000
11:6401431:T:A	acceptor_loss	1.0000
11:6402084:T:TA	donor_gain	1.0000
11:6402574:A:AC	donor_gain	1.0000
11:6402575:C:CC	donor_gain	1.0000
11:6402577:T:TA	donor_gain	1.0000
11:6402578:C:A	donor_gain	1.0000
11:6403400:TCATC:T	acceptor_gain	1.0000
11:6403401:CATC:C	acceptor_gain	1.0000
11:6403401:CATCC:C	acceptor_gain	1.0000

AlphaMissense

4625 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:6395823:G:T	A643D	1.000
11:6395834:G:C	C639W	1.000
11:6395849:G:C	C634W	1.000
11:6395886:G:T	A622E	1.000
11:6395918:G:C	F611L	1.000
11:6395918:G:T	F611L	1.000
11:6395920:A:G	F611L	1.000
11:6396119:A:G	L590P	1.000
11:6396140:A:T	V583D	1.000
11:6401003:A:T	V553D	1.000
11:6401593:A:G	L495P	1.000
11:6401602:G:T	A492D	1.000
11:6401605:A:T	I491N	1.000
11:6401614:G:T	A488D	1.000
11:6401625:A:C	C484W	1.000
11:6401626:C:T	C484Y	1.000
11:6401627:A:G	C484R	1.000
11:6401631:A:C	F482L	1.000
11:6401631:A:T	F482L	1.000
11:6401632:A:C	F482C	1.000
11:6401632:A:G	F482S	1.000
11:6401633:A:G	F482L	1.000
11:6401635:A:T	V481E	1.000
11:6401639:G:C	H480D	1.000
11:6401640:G:C	C479W	1.000
11:6401641:C:T	C479Y	1.000
11:6401642:A:G	C479R	1.000
11:6401678:A:C	Y467D	1.000
11:6401678:A:G	Y467H	1.000
11:6401678:A:T	Y467N	1.000

dbSNP variants (sampled 300 via entrez): RS1000069699 (11:6414206 T>TA), RS1000234926 (11:6401829 T>C), RS1000292870 (11:6407969 C>T), RS1000298240 (11:6395130 G>A), RS1000327510 (11:6395429 T>C), RS1000467816 (11:6418095 G>A,C), RS1000518728 (11:6398296 C>A), RS1000604566 (11:6417816 A>C), RS1000725049 (11:6407850 G>A), RS1000790020 (11:6412909 C>T), RS1001059431 (11:6397885 G>A,C), RS1001160085 (11:6412683 C>T), RS1001257807 (11:6419739 G>T), RS1001609235 (11:6402432 T>A), RS1001757553 (11:6417042 C>A)

Disease associations

OMIM: gene MIM:602709 | disease phenotypes: MIM:257200, MIM:607616, MIM:180860

GenCC curated gene-disease

Mondo (4): Niemann-Pick disease (MONDO:0001982), Niemann-Pick disease type A (MONDO:0009756), Niemann-Pick disease type B (MONDO:0011871), Silver-Russell syndrome (MONDO:0008394)

Orphanet (3): Infantile neurovisceral acid sphingomyelinase deficiency (Orphanet:77292), Chronic visceral acid sphingomyelinase deficiency (Orphanet:77293), Silver-Russell syndrome (Orphanet:813)

HPO phenotypes

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

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST010725_20	Malaria	4.000000e-69
GCST010725_33	Malaria	2.000000e-67
GCST010725_51	Malaria	1.000000e-55

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D052536	Niemann-Pick Disease, Type A	C10.228.140.163.100.435.825.700.500; C15.604.250.410.625.500; C16.320.565.189.435.825.700.500; C16.320.565.398.641.803.730.500; C16.320.565.595.554.825.700.500; C18.452.132.100.435.825.700.500; C18.452.584.563.641.803.730.500; C18.452.648.189.435.825.700.500; C18.452.648.398.641.803.730.500; C18.452.648.595.554.825.700.500
D052537	Niemann-Pick Disease, Type B	C10.228.140.163.100.435.825.700.750; C15.604.250.410.625.750; C16.320.565.189.435.825.700.750; C16.320.565.398.641.803.730.750; C16.320.565.595.554.825.700.750; C18.452.132.100.435.825.700.750; C18.452.584.563.641.803.730.750; C18.452.648.189.435.825.700.750; C18.452.648.398.641.803.730.750; C18.452.648.595.554.825.700.750
D009542	Niemann-Pick Diseases	C10.228.140.163.100.435.825.700; C15.604.250.410.625; C16.320.565.189.435.825.700; C16.320.565.398.641.803.730; C16.320.565.595.554.825.700; C18.452.132.100.435.825.700; C18.452.584.563.641.803.730; C18.452.648.189.435.825.700; C18.452.648.398.641.803.730; C18.452.648.595.554.825.700
D056730	Silver-Russell Syndrome	C05.660.207.925; C16.131.077.855; C16.131.260.870; C16.320.180.870; C16.320.240.937; C16.320.447.750

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1079199	APBB1		0.00	0

CTD chemical–gene interactions

23 total (human), top 23 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Arsenic Trioxide	decreases expression	2
Benzo(a)pyrene	affects methylation, increases methylation	2
aristolochic acid I	increases expression	1
FR900359	decreases phosphorylation	1
uranyl acetate	affects expression	1
bisphenol A	increases methylation, affects cotreatment, affects methylation	1
sodium arsenite	decreases expression	1
aflatoxin B2	decreases methylation	1
S-(1,2-dichlorovinyl)cysteine	affects cotreatment, decreases expression	1
abrine	increases expression	1
licochalcone B	increases expression	1
Sunitinib	decreases expression	1
Fulvestrant	affects cotreatment, affects methylation	1
Leflunomide	decreases expression	1
Arsenic	affects expression	1
Doxorubicin	increases expression	1
Lipopolysaccharides	affects cotreatment, decreases expression	1
Smoke	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Uranium	affects expression	1
Urethane	increases expression	1
Cadmium Chloride	increases expression	1
Zinc Sulfate	decreases expression	1

Cellosaurus cell lines

1 cell lines: 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B2RS	Abcam HEK293T APBB1 KO	Transformed cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT06457906	PHASE3	RECRUITING	SRS/SRT/Hypo-RT Versus HA-WBRT for No More Than 10 Brain Metastases in SCLC
NCT00668564	PHASE2	TERMINATED	Hematopoietic Stem Cell Transplantation (HCT) for Inborn Errors of Metabolism
NCT04180501	PHASE2	UNKNOWN	SRS Sequential Sindilimab in Brain Metastasis of NSLSC
NCT04899908	PHASE2	ACTIVE_NOT_RECRUITING	Stereotactic Brain-directed Radiation With or Without Aguix Gadolinium-Based Nanoparticles in Brain Metastases
NCT07162246	PHASE2	RECRUITING	Combined Gamma Knife/Linac Radiosurgery for Large Brain Tumors / Metastases
NCT00316498	PHASE1	COMPLETED	Saccadic Eye Movements in Patients With Niemann-Pick Type C Disease
NCT00410566	PHASE1	TERMINATED	Safety Study of rhASM Enzyme Replacement Therapy in Adults With Acid Sphingomyelinase Deficiency (Niemann-Pick Disease)
NCT01586455	PHASE1	COMPLETED	Human Placental-Derived Stem Cell Transplantation
NCT00176904	PHASE2/PHASE3	COMPLETED	Stem Cell Transplant for Inborn Errors of Metabolism
NCT00730314	PHASE1/PHASE2	COMPLETED	Unrelated Hematopoietic Stem Cell Transplantation(HSCT) for Genetic Diseases of Blood Cells
NCT01372228	PHASE1/PHASE2	TERMINATED	Phase I/II Pilot Study of Mixed Chimerism to Treat Inherited Metabolic Disorders
NCT00001972	Not specified	COMPLETED	PET Scan of Brain Metabolism in Relation to Age and Disease
NCT00005900	Not specified	UNKNOWN	Study of Pulmonary Complications in Pediatric Patients With Storage Disorders Undergoing Allogeneic Hematopoietic Stem Cell Transplantation
NCT01306604	Not specified	WITHDRAWN	Biomarker for Niemann Pick Type C Disease (BioNPC)
NCT02120235	Not specified	UNKNOWN	Investigating Lysosomal Storage Diseases in Minority Groups
NCT03333200	Not specified	RECRUITING	Longitudinal Study of Neurodegenerative Disorders
NCT03883750	Not specified	COMPLETED	Induced Pluripotent Stem Cells for Niemann Pick Disease
NCT04469894	Not specified	COMPLETED	Health Insurance Literacy and Challenges in Accessing Health Services in Niemann-Pick
NCT05641103	Not specified	COMPLETED	PREDIGA 2: Spanish Acronym of Educational and Diagnostic Project for Gaucher and ASMD
NCT06192576	Not specified	RECRUITING	A Real-world Long-term Safety and Immunogenicity Study of Olipudase Alfa Therapy in Pediatric Patients Less Than 2 Years of Age With Acid Sphingomyelinase Deficiency (ASMD)
NCT06985212	Not specified	NOT_YET_RECRUITING	National Multicentre Study of the Natural History of Acid Sphingo-myelinase Deficiency in Adults and Children
NCT07545473	Not specified	RECRUITING	Retinal Hyperspectral Imaging in Neurodegenerative Diseases
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns
NCT01520467	Not specified	UNKNOWN	Aromatase Inhibitor in Bone Maturation, Children With Silver Russell or Prader-Willi Syndrome
NCT03915106	Not specified	RECRUITING	Quality of Life (HRQoL) of AIS Patients Who Require Bracing or Surgery Using SRS-22 Questionnaire
NCT05070234	Not specified	UNKNOWN	Genetic Diagnosis and Human Growth Hormone Treatment in Small for Gestational Age Children With Short Stature
NCT05945576	Not specified	RECRUITING	IDMet (RaDiCo Cohort) (RaDiCo-IDMet)
NCT06466720	Not specified	ACTIVE_NOT_RECRUITING	Measuring and Mapping Cognitive Decline After Brain Radiosurgery
NCT06852001	Not specified	NOT_YET_RECRUITING	Efficacy of the RayerKnife X Stereotactic Radiotherapy System in the Treatment of Brain Metastases
NCT07405112	Not specified	COMPLETED	Impact of Curve Magnitude on Pain and Body Image in Patients With Adolescents Idiopathic Scoliosis