PPBP

Summary

PPBP (pro-platelet basic protein, HGNC:9240) is a protein-coding gene on chromosome 4q13.3, encoding Platelet basic protein (P02775). LA-PF4 stimulates DNA synthesis, mitosis, glycolysis, intracellular cAMP accumulation, prostaglandin E2 secretion, and synthesis of hyaluronic acid and sulfated glycosaminoglycan.

The protein encoded by this gene is a platelet-derived growth factor that belongs to the CXC chemokine family. This growth factor is a potent chemoattractant and activator of neutrophils. It has been shown to stimulate various cellular processes including DNA synthesis, mitosis, glycolysis, intracellular cAMP accumulation, prostaglandin E2 secretion, and synthesis of hyaluronic acid and sulfated glycosaminoglycan. It also stimulates the formation and secretion of plasminogen activator by synovial cells. The protein also is an antimicrobial protein with bactericidal and antifungal activity.

Source: NCBI Gene 5473 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 14 total
• MANE Select transcript: NM_002704

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9240
Approved symbol	PPBP
Name	pro-platelet basic protein
Location	4q13.3
Locus type	gene with protein product
Status	Approved
Aliases	SCYB7, TGB, NAP-2-L1, LA-PF4, MDGF, LDGF, Beta-TG, CTAP3, CXCL7, PBP, b-TG1, TGB1, CTAPIII, NAP-2
Ensembl gene	ENSG00000163736
Ensembl biotype	protein_coding
OMIM	121010
Entrez	5473

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000296028, ENST00000716905

RefSeq mRNA: 1 — MANE Select: NM_002704 NM_002704

CCDS: CCDS3563

Canonical transcript exons

ENST00000296028 — 3 exons

Exon	Start	End
ENSE00001077819	73987517	73987652
ENSE00004031056	73986439	73987374
ENSE00004031057	73987956	73988190

Expression profiles

Bgee: expression breadth ubiquitous, 170 present calls, max score 99.82.

FANTOM5 (CAGE): breadth broad, TPM avg 46.7862 / max 10819.2975, expressed in 263 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
52542	46.7862	263

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
monocyte	CL:0000576	99.82	gold quality
mononuclear cell	CL:0000842	99.80	gold quality
leukocyte	CL:0000738	99.66	gold quality
trabecular bone tissue	UBERON:0002483	99.54	gold quality
granulocyte	CL:0000094	96.63	gold quality
blood	UBERON:0000178	95.87	gold quality
bone marrow cell	CL:0002092	95.71	gold quality
bone marrow	UBERON:0002371	95.60	gold quality
periodontal ligament	UBERON:0008266	93.44	gold quality
spleen	UBERON:0002106	86.60	gold quality
decidua	UBERON:0002450	85.53	gold quality
right lung	UBERON:0002167	85.00	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	82.62	silver quality
biceps brachii	UBERON:0001507	77.54	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	76.87	gold quality
upper lobe of left lung	UBERON:0008952	76.20	gold quality
mucosa of paranasal sinus	UBERON:0005030	75.69	gold quality
placenta	UBERON:0001987	75.67	gold quality
upper lobe of lung	UBERON:0008948	75.61	gold quality
lower lobe of lung	UBERON:0008949	75.44	silver quality
lung	UBERON:0002048	73.72	gold quality
adrenal tissue	UBERON:0018303	72.63	gold quality
embryo	UBERON:0000922	67.81	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	66.92	gold quality
palpebral conjunctiva	UBERON:0001812	65.16	gold quality
superficial temporal artery	UBERON:0001614	64.86	silver quality
ganglionic eminence	UBERON:0004023	63.82	gold quality
pigmented layer of retina	UBERON:0001782	63.66	gold quality
germinal epithelium of ovary	UBERON:0001304	63.21	gold quality
right lobe of liver	UBERON:0001114	61.01	gold quality

Single-cell (SCXA)

Detected in 18 experiment(s), a significant marker in 18.

Experiment	Marker?	Max mean expression
E-MTAB-9221	yes	71562.29
E-MTAB-10432	yes	70099.31
E-GEOD-149689	yes	66792.10
E-GEOD-139324	yes	49682.83
E-MTAB-8207	yes	43232.81
E-MTAB-6701	yes	39334.17
E-HCAD-10	yes	33186.07
E-HCAD-4	yes	32584.02
E-HCAD-1	yes	21587.56
E-CURD-55	yes	10846.02
E-HCAD-32	yes	7665.85
E-HCAD-9	yes	6358.62
E-GEOD-150728	yes	6145.16
E-MTAB-9467	yes	5928.96
E-CURD-120	yes	1253.05

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): MYC, SPI1, TBP

miRNA regulators (miRDB)

53 targeting PPBP, 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-4795-3P	100.00	74.62	4024
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-10401-5P	99.99	65.79	948
HSA-MIR-6759-5P	99.99	66.54	785
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-146A-5P	99.96	68.93	988
HSA-MIR-146B-5P	99.96	69.13	977
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-7153-5P	99.94	68.89	1006
HSA-MIR-4760-3P	99.93	70.50	2385
HSA-MIR-6508-5P	99.92	70.67	2465
HSA-MIR-6783-3P	99.89	67.92	2059
HSA-MIR-1343-3P	99.89	66.78	1815
HSA-MIR-8067	99.86	69.59	2260
HSA-MIR-374C-5P	99.80	72.06	2910
HSA-MIR-655-3P	99.80	72.19	2909
HSA-MIR-4524A-3P	99.72	66.85	2406
HSA-MIR-4441	99.49	66.56	3216
HSA-MIR-122B-5P	99.46	70.81	1457
HSA-MIR-5009-3P	99.45	69.43	1341
HSA-MIR-3140-5P	99.39	69.04	1136
HSA-MIR-6507-5P	99.36	70.46	2524
HSA-MIR-148A-5P	99.30	68.27	1141
HSA-MIR-6739-3P	99.22	68.84	1843
HSA-MIR-296-3P	99.21	66.56	474
HSA-MIR-1911-3P	99.15	66.17	528
HSA-MIR-3688-5P	99.12	69.67	1091
HSA-MIR-3152-3P	99.10	66.35	678

Literature-anchored findings (GeneRIF, showing 40)

• Pointed, an activator, and Tramtrack69, a repressor, directly regulate the transcription of string and thereby cell proliferation (PMID:12447387)
• Induction of stg rescues the neuroblast proliferation defect in trol mutant animals. (PMID:12929089)
• string(cdc25) and cyclin E control patterned histone expression at different stages of Drosophila embryonic development. (PMID:15355790)
• EYA and SO may influence cell proliferation through transcriptional regulation of stg. (PMID:17714699)
• String and dappled were identified as being important for the proper formation of adult external sensory (ES) organs. (PMID:18420029)
• double-stranded RNA-mediated depletion of dPrp38 or dMFAP1 causes cells to arrest in G(2)/M, and this is paralleled by a reduction in mRNA levels of the mitotic phosphatase string/cdc25. (PMID:18765666)
• Thereby, we show that abdominal histoblasts, which grow while in G2 arrest during larval stages, enter a proliferative stage in the pupal period that is initiated by ecdysone-dependent string/Cdc25 phosphatase transcription. (PMID:19355788)
• SIN3 and STG are linked in a genetic pathway that affects cell cycle progression in a developing tissue (PMID:19825413)
• String (Cdc25) regulates stem cell maintenance, proliferation and aging in Drosophila testis. (PMID:22031544)
• findings suggest that high Cdc25 and Cdk1 contribute to the speed of the rapid, pre-midblastula transition (MBT) S phases and that down-regulation of these activities plays a broader role in MBT-associated changes than was previously suspected (PMID:22431511)
• Premature removal of cdc25 transcripts by RNAi did not affect progression to the midblastula transition. (PMID:23290551)
• The degradation rate of String protein gradually increases during the late syncytial cycles in a manner dependent on the nuclear-to-cytoplasmic ratio and on the DNA replication checkpoints. (PMID:23290553)
• we show that during the development of epithelial cells in the imaginal discs, the G2/M transition, and hence cell proliferation, is controlled by Emc via Da. In eukaryotic cells, the main activator of this transition is the Cdc25 phosphatase, string (PMID:24651265)
• The antimicrobial thrombocidin peptides are found in human blood platelets, are deletion products of CXC chemokines and have antibacterial and antifungal activity. (PMID:10877842)
• CXCL7 promotes neutrophil adhesion to vascular endothelium and induces transendothelial migration. (PMID:12193731)
• one or more high molecular weight protein is released from alpha-granules and is broken down into smaller fragments after release to form beta-thromboglobulin (beta-TG)-like proteins by the action of metal dependent proteases. (PMID:12297130)
• Gene profiling iodentified PPBP from peripheral blood cells in coronary artery disease. (PMID:12878486)
• Platelet basic protein is downregulated by glucocorticoids, and is defined as an immunosuppressive target of glucocorticoids. (PMID:14673015)
• Our observations indicate that PBP and its derivates are constituents of the antimicrobial arsenal of human monocytes. Their increased expression after exposure to microorganisms allows a rapid host response to pathogens. (PMID:15316029)
• activated human skin mast cells (MCs) convert CTAP-III into biologically active NAP-2 through proteolytic cleavage by released chymase. (PMID:16317101)
• stromal-stimulated monocytes can serve as an additional source for CXCL7 peptides in the microenvironment and may contribute to the local regulation of megakaryocytopoiesis (PMID:16391012)
• levels of BDNF and beta-TG in blood of Alzheimers patients is decreased; BDNF and beta-TG are associated with degree of platelet activation (PMID:16807663)
• NAP-2 has the potential to induce inflammatory responses within the atherosclerotic plaque. By its ability to promote leukocyte and endothelial cell activation, such a NAP-2-driven inflammation could promote plaque rupture and acute coronary syndromes. (PMID:17045893)
• CXCL7 decreased serum levels in advanced MDS, suggesting the possibility of a concerted disturbance of transcription or translation of these chemokines in advanced MDS (PMID:17220270)
• delayed pressure urticaria may be associated with increased secretion of platelet chemokines PF4 and beta-TG, similar to that observed in cold urticaria (PMID:18632422)
• stimulates the migration of mesenchymal stem cells in vitro (PMID:18707017)
• beta-TG is cleaved after being released from activated platelets, thereby becoming less mitogenic for fibroblasts (PMID:20224257)
• Using microdialysis techniques we detected beta-TG release during an inflammatory response. We conclude that local platelet activation is induced by the heating stimulus. (PMID:20510637)
• positive ratios of CXCR7, CXCL12 and CXCL11 in oral leukoplakia and oral squamous cell carcinoma tissues respectively, were significantly higher than that in normal epithelia (PMID:21442287)
• modulates antimicrobial activity of phagocytes against L. pneumophila (PMID:22101183)
• Examined the prognostic values of SARS-associated proteome, and deciphered the identities of those with prognostic values.The associations of decreased serum PF4 and increased serum beta-TG levels with poor prognosis were confirmed by Western blot. (PMID:22740477)
• beta-TG was evaluated for familial mediterranean fever cases and healthy controls, beta-TG levels were found significantly lower among patients; it is hypothesized that this difference may have resulted from the effect of colchicine use on platelet functions. (PMID:22939812)
• The level of beta-thromboglobulin was found significantly higher in female patients with rheumatoid arthritis. (PMID:23052484)
• Testing of bacterial resistance to platelet antimicrobial lmw proteins (PMPs) may be advisable as a predictive indicator of susceptibility to treatment of infections such as infective endocarditis and other local infections of biofilm nature. (PMID:23619231)
• CXCR4-CXCL12-CXCR7 regulates mTOR signaling in renal cancer cells. (PMID:24991762)
• CXCL7/CXCR2 signalling pathways are a predictive factor of poor outcome in metastatic colon cancer. (PMID:25580640)
• Synovial Cxcl7 mRNA and protein were increased in early rheumatoid arthritis compared to uninflamed controls and resolving arthritis. (PMID:25858640)
• Leptin and neutrophil-activating peptide act synergistically to promote mesenchymal stem cell senescence through enhancement of the PI3K/Akt signaling pathway in systemic lupus erythematosus patients. (PMID:25989537)
• Studied and characterized the dynamics and thermodynamic stability of monomer and homodimer structures of CXCL7. (PMID:26297927)
• Utilizing mass spectrometry-based proteomics, platelet basic protein has been identified as a candidate serum biomarker for transient ischemic attack (PMID:26307429)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	cxcl18b	ENSDARG00000075045
danio_rerio	cxcl20	ENSDARG00000075163
danio_rerio		ENSDARG00000114454
mus_musculus	Ppbp	ENSMUSG00000029372
rattus_norvegicus	Ppbp	ENSRNOG00000002829

Paralogs (12): CXCL2 (ENSG00000081041), PF4V1 (ENSG00000109272), CXCL6 (ENSG00000124875), CXCL9 (ENSG00000138755), CXCL13 (ENSG00000156234), CXCL3 (ENSG00000163734), CXCL5 (ENSG00000163735), PF4 (ENSG00000163737), CXCL1 (ENSG00000163739), CXCL10 (ENSG00000169245), CXCL11 (ENSG00000169248), CXCL8 (ENSG00000169429)

Protein

Protein identifiers

Platelet basic protein — P02775 (reviewed: P02775)

Alternative names: C-X-C motif chemokine 7, Leukocyte-derived growth factor, Macrophage-derived growth factor, Small-inducible cytokine B7

All UniProt accessions (1): P02775

UniProt curated annotations — full annotation on UniProt →

Function. LA-PF4 stimulates DNA synthesis, mitosis, glycolysis, intracellular cAMP accumulation, prostaglandin E2 secretion, and synthesis of hyaluronic acid and sulfated glycosaminoglycan. It also stimulates the formation and secretion of plasminogen activator by human synovial cells. NAP-2 is a ligand for CXCR1 and CXCR2, and NAP-2, NAP-2(73), NAP-2(74), NAP-2(1-66), and most potent NAP-2(1-63) are chemoattractants and activators for neutrophils. TC-1 and TC-2 are antibacterial proteins, in vitro released from activated platelet alpha-granules. CTAP-III(1-81) is more potent than CTAP-III desensitize chemokine-induced neutrophil activation.

Subunit / interactions. Beta-thromboglobulin is a homotetramer.

Subcellular location. Secreted.

Post-translational modifications. Proteolytic removal of residues 1-9 produces the active peptide connective tissue-activating peptide III (CTAP-III) (low-affinity platelet factor IV (LA-PF4)). Proteolytic removal of residues 1-13 produces the active peptide beta-thromboglobulin, which is released from platelets along with platelet factor 4 and platelet-derived growth factor. NAP-2(1-66) is produced by proteolytical processing, probably after secretion by leukocytes other than neutrophils. NAP-2(73) and NAP-2(74) seem not be produced by proteolytical processing of secreted precursors but are released in an active form from platelets.

Similarity. Belongs to the intercrine alpha (chemokine CxC) family.

RefSeq proteins (1): NP_002695* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001089	Chemokine_CXC	Family
IPR001811	Chemokine_IL8-like_dom	Domain
IPR018048	Chemokine_CXC_CS	Conserved_site
IPR033899	CXC_Chemokine_domain	Domain
IPR036048	Interleukin_8-like_sf	Homologous_superfamily
IPR039809	Chemokine_b/g/d	Family

Pfam: PF00048

UniProt features (22 total): chain 11, strand 5, helix 3, disulfide bond 2, signal peptide 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
1TVX	X-RAY DIFFRACTION	1.75
1NAP	X-RAY DIFFRACTION	1.9
1F9P	X-RAY DIFFRACTION	1.93

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P02775-F1	77.64	0.45

Functional residue map

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

Disulfide bonds (2): 63–89, 65–105

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-114608	Platelet degranulation
R-HSA-380108	Chemokine receptors bind chemokines
R-HSA-418594	G alpha (i) signalling events
R-HSA-6798695	Neutrophil degranulation

MSigDB gene sets: 257 (showing top): DAVIES_MULTIPLE_MYELOMA_VS_MGUS_DN, GOBP_CARBOHYDRATE_TRANSPORT, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_ANTIMICROBIAL_HUMORAL_RESPONSE, GOBP_MYELOID_LEUKOCYTE_MIGRATION, GOBP_CELL_CHEMOTAXIS, GOBP_INFLAMMATORY_RESPONSE, GOBP_CELLULAR_RESPONSE_TO_LIPID, GOCC_SECRETORY_GRANULE, REACTOME_PLATELET_ACTIVATION_SIGNALING_AND_AGGREGATION, ENK_UV_RESPONSE_KERATINOCYTE_UP, GOBP_CELLULAR_RESPONSE_TO_BIOTIC_STIMULUS, MODULE_45, MODULE_64, MATTIOLI_MGUS_VS_PCL

GO Biological Process (11): inflammatory response (GO:0006954), neutrophil chemotaxis (GO:0030593), defense response to bacterium (GO:0042742), positive regulation of cell division (GO:0051781), antimicrobial humoral immune response mediated by antimicrobial peptide (GO:0061844), cellular response to lipopolysaccharide (GO:0071222), D-glucose transmembrane transport (GO:1904659), chemotaxis (GO:0006935), defense response (GO:0006952), immune response (GO:0006955), signal transduction (GO:0007165)

GO Molecular Function (6): chemokine activity (GO:0008009), growth factor activity (GO:0008083), CXCR chemokine receptor binding (GO:0045236), D-glucose transmembrane transporter activity (GO:0055056), cytokine activity (GO:0005125), protein binding (GO:0005515)

GO Cellular Component (4): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), platelet alpha granule lumen (GO:0031093), tertiary granule lumen (GO:1904724)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Response to elevated platelet cytosolic Ca2+	1
Peptide ligand-binding receptors	1
GPCR downstream signalling	1
Innate Immune System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
defense response	2
chemokine receptor binding	2
receptor ligand activity	2
granulocyte chemotaxis	1
neutrophil migration	1
response to bacterium	1
positive regulation of cellular process	1
cell division	1
regulation of cell division	1
antimicrobial humoral response	1
response to lipopolysaccharide	1
cellular response to molecule of bacterial origin	1
cellular response to lipid	1
cellular response to oxygen-containing compound	1
hexose transmembrane transport	1
response to chemical	1
taxis	1
response to stress	1
immune system process	1
response to stimulus	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
cytokine activity	1
cell chemotaxis	1
hexose transmembrane transporter activity	1
binding	1
cellular anatomical structure	1
platelet alpha granule	1
secretory granule lumen	1
intracellular organelle lumen	1
tertiary granule	1

Protein interactions and networks

STRING

1948 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PPBP	CXCR2	P25025	996
PPBP	CXCR1	P25024	993
PPBP	CXCL12	P48061	934
PPBP	CXCL10	P02778	932
PPBP	CCR2	P41597	923
PPBP	CXCR4	P30991	890
PPBP	CXCL11	O14625	878
PPBP	SELP	P16109	862
PPBP	ACKR1	Q16570	834
PPBP	CXCL1	P09341	793
PPBP	VWF	P04275	759
PPBP	CCR5	P51681	745
PPBP	CXCR3	P49682	734
PPBP	IFNG	P01579	731
PPBP	FGA	P02671	725

IntAct

46 interactions, top by confidence:

A	B	Type	Score
PPBP	CCL5	psi-mi:“MI:0407”(direct interaction)	0.560
CCK	PPBP	psi-mi:“MI:0915”(physical association)	0.560
SH3GLB1	PPBP	psi-mi:“MI:0915”(physical association)	0.560
PRPF40A	PPBP	psi-mi:“MI:0915”(physical association)	0.560
EFNA1	PPBP	psi-mi:“MI:0915”(physical association)	0.550
PPBP	CCL13	psi-mi:“MI:0407”(direct interaction)	0.440
PPBP	CCL21	psi-mi:“MI:0407”(direct interaction)	0.440
PPBP	CCL26	psi-mi:“MI:0407”(direct interaction)	0.440
PPBP	CCL28	psi-mi:“MI:0407”(direct interaction)	0.440
CCL8	PPBP	psi-mi:“MI:0407”(direct interaction)	0.440
CXCL6	PPBP	psi-mi:“MI:0407”(direct interaction)	0.440
CXCL9	PPBP	psi-mi:“MI:0407”(direct interaction)	0.440
PPBP	CXCL9	psi-mi:“MI:0407”(direct interaction)	0.440
PPBP	CXCL10	psi-mi:“MI:0407”(direct interaction)	0.440
PPBP	CXCL11	psi-mi:“MI:0407”(direct interaction)	0.440
PPBP	CXCL12	psi-mi:“MI:0407”(direct interaction)	0.440
PPBP	CXCL14	psi-mi:“MI:0407”(direct interaction)	0.440
	CD5L	psi-mi:“MI:0915”(physical association)	0.400
COPG1	PPBP	psi-mi:“MI:0915”(physical association)	0.370
CMTM6	PPBP	psi-mi:“MI:0915”(physical association)	0.370
PPBP	MAPK6	psi-mi:“MI:0915”(physical association)	0.370
PPBP	MOB3B	psi-mi:“MI:0915”(physical association)	0.370
PPBP	NDUFB11	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (32): PPBP (Two-hybrid), PPBP (Two-hybrid), PPBP (Two-hybrid), PPBP (Two-hybrid), PPBP (Co-crystal Structure), PPBP (Reconstituted Complex), PPBP (Reconstituted Complex), CCL13 (Reconstituted Complex), CCL21 (Reconstituted Complex), CCL26 (Reconstituted Complex), CCL28 (Reconstituted Complex), CCL5 (Reconstituted Complex), CXCL10 (Reconstituted Complex), CXCL11 (Reconstituted Complex), CXCL12 (Reconstituted Complex)

ESM2 similar proteins: A0A0R4INB9, A9QWP9, B0R191, K7XWG4, O00175, O35903, O43927, O55038, O62812, O70460, P02775, P02778, P10146, P10720, P17515, P18340, P22362, P26894, P27784, P28292, P41324, P43030, P47992, P47993, P48298, P48973, P49113, P50228, P51672, P79255, P84444, P86792, P86793, P97545, P97885, Q07325, Q08782, Q2KIQ8, Q5KSV9, Q62401

Diamond homologs: A0A0R4INB9, A9QWP9, A9QWQ1, B0R191, O14625, O46678, P02775, P02778, P08317, P09341, P12850, P17515, P19875, P19876, P22952, P42830, P48973, P50228, P80162, P80221, P82535, P97885, Q07325, Q2KIQ8, Q5KSV9, Q865F5, Q8MIZ1, Q9JHH5, O46675, O46676, O46677, O55235, O62812, P02776, P06765, P09340, P10145, P10720, P10889, P14095

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
PPBP	“down-regulates activity”	OPRD1	“chemical inhibition”
PPBP	“down-regulates activity”	OPRM1	“chemical inhibition”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 37 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
Chemokine receptors bind chemokines	9	70.2×	4e-13
Class A/1 (Rhodopsin-like receptors)	6	18.5×	2e-05
Peptide ligand-binding receptors	6	18.5×	2e-05
GPCR ligand binding	6	16.0×	4e-05
G alpha (i) signalling events	9	14.6×	3e-07
GPCR downstream signalling	6	10.9×	3e-04
Signaling by GPCR	6	10.0×	5e-04

GO biological processes:

GO term	Partners	Fold	FDR
eosinophil chemotaxis	5	107.8×	4e-08
chemokine-mediated signaling pathway	10	95.3×	1e-15
chemotaxis	11	44.0×	8e-14
antimicrobial humoral immune response mediated by antimicrobial peptide	8	38.1×	2e-09
cell-cell signaling	10	20.5×	2e-09
inflammatory response	12	13.3×	2e-09
positive regulation of cell migration	6	10.9×	4e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	14
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

215 predictions. Top by Δscore:

Variant	Effect	Δscore
4:73987373:CT:C	acceptor_gain	0.9900
4:73987375:C:CC	acceptor_gain	0.9900
4:73987515:A:AC	donor_gain	0.9900
4:73987516:C:CC	donor_gain	0.9900
4:73987516:CATCA:C	donor_gain	0.9900
4:73987370:TGGCT:T	acceptor_gain	0.9800
4:73987374:TC:T	acceptor_loss	0.9800
4:73987375:C:CA	acceptor_loss	0.9800
4:73987376:T:G	acceptor_loss	0.9800
4:73987516:CAT:C	donor_gain	0.9800
4:73987371:GGCT:G	acceptor_gain	0.9700
4:73987372:GCT:G	acceptor_gain	0.9700
4:73987373:CTC:C	acceptor_gain	0.9700
4:73987374:TCT:T	acceptor_gain	0.9700
4:73987510:AACTT:A	donor_loss	0.9600
4:73987511:ACTT:A	donor_loss	0.9600
4:73987512:CTTAC:C	donor_loss	0.9600
4:73987513:TTA:T	donor_loss	0.9600
4:73987514:T:TG	donor_loss	0.9600
4:73987515:A:AT	donor_loss	0.9600
4:73987509:CAACT:C	donor_loss	0.9500
4:73987515:ACAT:A	donor_gain	0.9400
4:73987516:CA:C	donor_gain	0.9400
4:73987516:CATC:C	donor_gain	0.9400
4:73987523:TCG:T	donor_gain	0.9400
4:73987610:A:C	acceptor_gain	0.9400
4:73987651:CT:C	acceptor_gain	0.9200
4:73987653:C:CC	acceptor_gain	0.9200
4:73987960:G:A	donor_gain	0.9200
4:73987955:CCT:C	donor_gain	0.9100

AlphaMissense

829 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:73987372:G:T	A96D	0.997
4:73987535:C:G	C89S	0.995
4:73987536:A:T	C89S	0.995
4:73987345:C:G	C105S	0.993
4:73987346:A:T	C105S	0.993
4:73987607:C:G	C65S	0.991
4:73987608:A:T	C65S	0.991
4:73987613:C:G	C63S	0.991
4:73987614:A:T	C63S	0.991
4:73987346:A:G	C105R	0.990
4:73987535:C:T	C89Y	0.990
4:73987373:C:G	A96P	0.988
4:73987535:C:A	C89F	0.987
4:73987536:A:G	C89R	0.987
4:73987534:G:C	C89W	0.986
4:73987366:A:G	L98P	0.985
4:73987342:A:T	L106Q	0.983
4:73987608:A:G	C65R	0.983
4:73987344:G:C	C105W	0.982
4:73987342:A:G	L106P	0.981
4:73987562:A:G	L80S	0.981
4:73987345:C:T	C105Y	0.980
4:73987571:A:C	I77S	0.980
4:73987571:A:T	I77N	0.980
4:73987614:A:G	C63R	0.980
4:73987522:T:A	E93D	0.978
4:73987522:T:G	E93D	0.978
4:73987346:A:C	C105G	0.977
4:73987571:A:G	I77T	0.975
4:73987606:A:C	C65W	0.970

dbSNP variants (sampled 300 via entrez): RS1001814023 (4:73986297 C>T), RS1002657820 (4:73988627 G>C), RS1002693408 (4:73987108 A>G), RS1002697696 (4:73988189 G>A,C), RS1003223456 (4:73987822 C>A,G,T), RS1004106192 (4:73989484 A>G), RS1004200568 (4:73988097 G>T), RS1004873874 (4:73986614 T>C), RS1005095065 (4:73986937 C>T), RS1005874270 (4:73988276 T>A), RS1006620736 (4:73986441 A>G), RS1007222550 (4:73989142 A>G), RS1007334042 (4:73988904 T>C,G), RS1008170819 (4:73989193 T>C), RS1008745152 (4:73989972 G>A)

Disease associations

OMIM: gene MIM:121010 | 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
GCST001639_7	Metabolite levels	3.000000e-10

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004723	coronary artery calcification

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Lipopolysaccharides	increases expression, affects reaction, affects expression	3
chloropicrin	decreases expression, increases expression	2
Nickel	increases expression, increases secretion, affects binding	2
Cadmium Chloride	increases reaction, decreases expression, decreases secretion	2
triphenyl phosphate	affects expression	1
cinnamaldehyde	increases expression, increases secretion	1
sodium arsenite	increases expression	1
butyraldehyde	increases expression	1
styrofoam	increases secretion	1
CGP 52608	increases reaction, affects binding	1
thrombin receptor-activating peptide SFLLRNPNDKY	decreases reaction, increases secretion	1
entinostat	decreases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	increases expression	1
NSC 689534	increases expression	1
Zoledronic Acid	increases expression	1
Arsenic Trioxide	increases expression	1
Acetylcysteine	decreases secretion, increases reaction	1
Adenosine Diphosphate	increases secretion	1
Air Pollutants	decreases expression, increases abundance	1
Arsenic	increases expression	1
Aspirin	decreases reaction, increases secretion	1
Atrazine	increases expression	1
Benzene	decreases expression	1
Benzo(a)pyrene	decreases methylation	1
Cadmium	affects binding	1
Cocaine	increases expression	1
Copper	affects binding	1
Environmental Pollutants	decreases expression	1
Eugenol	increases expression, increases secretion	1
Heparin	increases secretion	1

Clinical trials (associated diseases)

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