IGFBP5

Summary

IGFBP5 (insulin like growth factor binding protein 5, HGNC:5474) is a protein-coding gene on chromosome 2q35, encoding Insulin-like growth factor-binding protein 5 (P24593). Multifunctional protein that plays a critical role in regulating the availability of IGFs to their receptors and thereby regulates IGF-mediated cellular processes including proliferation, differentiation, and apoptosis in a cell-type specific manner.

Enables insulin-like growth factor I binding activity and receptor ligand activity. Involved in several processes, including cellular response to cAMP; regulation of smooth muscle cell migration; and regulation of smooth muscle cell proliferation. Part of insulin-like growth factor ternary complex. Biomarker of pulmonary fibrosis.

Source: NCBI Gene 3488 — RefSeq curated summary.

At a glance

• GWAS associations: 24
• Clinical variants (ClinVar): 42 total
• Druggable target: yes
• MANE Select transcript: NM_000599

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:5474
Approved symbol	IGFBP5
Name	insulin like growth factor binding protein 5
Location	2q35
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000115461
Ensembl biotype	protein_coding
OMIM	146734
Entrez	3488

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 3 protein_coding, 1 retained_intron

ENST00000233813, ENST00000449583, ENST00000486341, ENST00000957219

RefSeq mRNA: 1 — MANE Select: NM_000599 NM_000599

CCDS: CCDS2405

Canonical transcript exons

ENST00000233813 — 4 exons

Exon	Start	End
ENSE00000785613	216678112	216678231
ENSE00000785614	216678850	216679079
ENSE00000796861	216672105	216676882
ENSE00000796862	216694439	216695549

Expression profiles

Bgee: expression breadth ubiquitous, 302 present calls, max score 99.90.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 143.0919 / max 4570.1646, expressed in 1183 samples.

FANTOM5 promoters (26 alternative TSS)

Promoter ID	TPM avg	Samples expressed
33844	130.5344	1167
33781	1.9171	531
33789	1.7662	507
33830	1.4281	565
33833	1.2144	452
33837	0.7844	354
33836	0.7627	315
33832	0.6781	328
33838	0.5428	242
33804	0.4234	210

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
renal medulla	UBERON:0000362	99.90	gold quality
urethra	UBERON:0000057	99.89	gold quality
saphenous vein	UBERON:0007318	99.84	gold quality
nipple	UBERON:0002030	99.81	gold quality
vena cava	UBERON:0004087	99.80	gold quality
cardia of stomach	UBERON:0001162	99.77	gold quality
pylorus	UBERON:0001166	99.74	gold quality
endocervix	UBERON:0000458	99.73	gold quality
left uterine tube	UBERON:0001303	99.73	gold quality
right ovary	UBERON:0002118	99.69	gold quality
left ovary	UBERON:0002119	99.65	gold quality
synovial joint	UBERON:0002217	99.63	gold quality
pericardium	UBERON:0002407	99.63	gold quality
trachea	UBERON:0003126	99.57	gold quality
body of uterus	UBERON:0009853	99.54	gold quality
periodontal ligament	UBERON:0008266	99.53	gold quality
layer of synovial tissue	UBERON:0007616	99.52	gold quality
penis	UBERON:0000989	99.48	gold quality
body of tongue	UBERON:0011876	99.46	gold quality
dorsal root ganglion	UBERON:0000044	99.42	gold quality
myometrium	UBERON:0001296	99.42	gold quality
gluteal muscle	UBERON:0002000	99.37	gold quality
right lobe of thyroid gland	UBERON:0001119	99.35	gold quality
superficial temporal artery	UBERON:0001614	99.35	gold quality
metanephros cortex	UBERON:0010533	99.35	gold quality
pharyngeal mucosa	UBERON:0000355	99.34	gold quality
fundus of stomach	UBERON:0001160	99.34	gold quality
mammary duct	UBERON:0001765	99.29	gold quality
right coronary artery	UBERON:0001625	99.27	gold quality
trigeminal ganglion	UBERON:0001675	99.26	gold quality

Single-cell (SCXA)

Detected in 45 experiment(s), a significant marker in 43.

Experiment	Marker?	Max mean expression
E-GEOD-124472	yes	10905.17
E-GEOD-135922	yes	6653.61
E-CURD-79	yes	6454.44
E-HCAD-36	yes	6107.11
E-MTAB-9435	yes	5149.82
E-MTAB-10287	yes	5065.59
E-MTAB-9841	yes	4985.76
E-CURD-46	yes	4980.96
E-MTAB-8322	yes	4894.22
E-CURD-126	yes	4885.18
E-GEOD-134144	yes	4619.31
E-MTAB-10662	yes	3351.09
E-HCAD-5	yes	3341.50
E-GEOD-114530	yes	3121.29
E-MTAB-8559	yes	2988.21

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CEBPA, CEBPB, CEBPG, EGR2, ETV6, GATA4, MN1, MYB, MYBL2, MYF5, MYOD1, NFIC, PGR, RELA, SIX5, TFAP2A, TFAP2B

miRNA regulators (miRDB)

250 targeting IGFBP5, 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-3613-3P	100.00	76.36	7965
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-4776-3P	100.00	68.73	1340
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-4745-5P	99.98	65.95	1028
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-146A-5P	99.96	68.93	988
HSA-MIR-146B-5P	99.96	69.13	977
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-1236-3P	99.94	68.04	1695

Literature-anchored findings (GeneRIF, showing 40)

• Insulin-like growth factor-binding protein 5 (IGFBP-5) interacts with a four and a half LIM protein 2 (FHL2). (PMID:11821401)
• role in stimulating growth and IGF-I secretion in intestinal smooth muscle by ras-dependent activation of MAP kinase signaling pathways (PMID:11923300)
• c-Myb and B-Myb transactivate the IGFBP-5 promoter through binding-dependent and -independent mechanisms. (PMID:11973331)
• cDNA probes were used to analyze the gene expression of IGFBP-5 in luteinized granulosa cells from different-sized follicles after ovarian hyperstimulation. Transcript levels increased with increasing follicular fluid (FF) volume (PMID:12005306)
• IGFBP-5 is a potent growth inhibitor and proapoptotic agent in human breast cancer cells via modulation of cell cycle regulation and apoptotic mediators (PMID:12777377)
• Fibronectin and IGFBP-5 bind to each other, and this binding negatively regulates the ligand-dependent action of IGFBP-5 by triggering IGFBP-5 proteolysis. (PMID:14645245)
• The IGFBP-5 C-domain is necessary and sufficient for its nuclear localization, and residues K206, K208, K217, and K218 are particularly critical. The IGFBP-5 N-domain contains a putative transactivation domain. (PMID:15001525)
• IGF-II:VN and IGF-I:IGFBP-5:VN complexes may be useful in situations where enhanced keratinocyte cell migration and proliferation is required, such as in wound healing and skin regeneration. (PMID:15140223)
• exogenous IGFBP-5 increases apoptosis by binding to and inhibiting the activities of insulin-like growth factors (PMID:15155755)
• Understanding the mechanism of how cleavage of IGFBP-5 by this protease (IGFBPase) alters its activity will help to further our understanding of the biologic actions of the IGFs (PMID:15534875)
• Inhibition of expression of IGFBP-5 by micro and small interfering RNA has marked effect on neuroblastoma cell proliferation, apoptosis, and differentiation (PMID:15618969)
• IGFBP-5 has a role in growth and differentiation of neuroblastoma cells (PMID:15650232)
• The expression of certain IGFBP is significantly altered in renal cell carcinoma (PMID:15661050)
• Insulin-like growth factor binding proteins 3 and 5 are xpressed in idiopathic pulmonary fibrosis and have a role in extracellular matrix deposition (PMID:15681824)
• Activation by C/EBP alpha and beta did not depend on their binding to the C/EBP site, since they still activated IGFBP-5 promoter. (PMID:15777798)
• In that IGFBP-5 is thought to stimulate transgenic bone formation, directly or via the action of insulin-like growth factor 1, such changes in bone IGFBP-5 may be important to ensure robust bone acquisition in the early postnatal period. (PMID:15780948)
• IGFBP-5 expression may influence extrinsic apoptotic pathways via a differential modulation of downstream cell survival and cell death pathways. (PMID:15802501)
• Igfbp5-mediated fibroblast growth factor receptor 2-IIIb signals regulate the genetic program that controls the structure of the hair shaft medulla in transgenic mice. (PMID:15930103)
• IGFBP-5 interacts with RASSF1C (PMID:16007340)
• Importance of the kinetics of association/dissociation in determining the enhancing or inhibiting effects of IGFBP-5 and the ability to generate an IGFBP-5 mutant with exclusively IGF-enhancing activity. (PMID:16195401)
• In conclusion, our findings are consistent with the hypothesis that FHL-2 and ADAM-9 are important modulators of IGFBP-5 actions and are, in part, regulated in a coordinated manner in bone (PMID:16311053)
• there are several conserved residues in the IGFBP-5 N-terminal region that are critical for transactivation and IGFBP-2 and -3 also have strong transactivation activity in their N-domains (PMID:16543235)
• IGF-I and -II are chemotactic factors for mesenchymal progenitor cells; IGFBP-5 both modulates the IGF-I effect and directly stimulates migration of human mesenchymal progenitor cells (PMID:16716263)
• overexpression of IGFBP-5 may play a significant role in the malignant transformation of normal pancreatic epithelial cells (PMID:16865675)
• Inhibition of endogenously produced IGFBP-5 is associated with Bim-dependent apoptosis in NB cells. (PMID:17067554)
• Overexpression of IGFBP-5 in mouse lung results in fibroblast activation, increased extracellular matrix deposition, and myofibroblastic changes. (PMID:17071587)
• Promoter contains a CACCC-rich consensus sequence required for activation by MN1. (PMID:17242174)
• study shows that down-regulation of IGFBP-5 protein correlates with cervical carcinogenesis and does so at a preneoplastic stage (PMID:17290407)
• Ratios between the IGFBPs and IGF(insulin-like growth factor), different IGFBPs, sequential proteolytic cleavage of IGFBPs, and association of activating proteinases are elements in the regulation of IGF receptor stimulation. (PMID:17312271)
• A cDNA library consisting of 220 upregulated genes in tumour tissue was established and named as LSCC. Differential expression was confirmed in five of these genes, including IGFBP5, SQLE, RAP2B, CLDN1, and TBL1XR1. (PMID:17316888)
• Phosphorylation and O-glycosylation both affected IGFBP-5 binding to heparin but not insulin-like growth factor binding or ternary complex formation with the acid-labile subunit. (PMID:17496250)
• IGFBP-5 can interact with VDR to prevent RXR:VDR heterodimerization; IGFBP-5 may attenuate the 1,25(OH)2D3-induced expression of bone differentiation markers. (PMID:17595320)
• Overexpression of IGFBP5 was associated with breast cancer (PMID:17651454)
• IGFBP-5 plays a role in the regulation of cellular senescence via a p53-dependent pathway and in aging-associated vascular diseases (PMID:17804819)
• Androgen suppressive therapy increases IGFBP5 in the bone marrow microenvironment and thereby may facilitate the progression of prostate cancer. (PMID:17823924)
• Insulin-like growth factor-binding protein-5 enters vesicular structures but not the nucleus (PMID:17892529)
• This suggests that IGFBP-5 possesses an IGF-independent suppressor function (PMID:18085517)
• IGFBP-5 inducible by gankyrin overexpression may be involved human hepatocarcinogenesis. (PMID:18161051)
• Single nucleotide polymorphisms in IGFBP5 is associated with breast cancer (PMID:18210156)
• There is a novel function of ADAM-12m in chondrocyte proliferation and cloning in osteoarthritic cartilage through enhanced bioavailability of IGF-1 from the IGF-1-IGFBP-5 complex by selective IGFBP-5 digestion. (PMID:18311789)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	igfbp5b	ENSDARG00000025348
danio_rerio	igfbp5a	ENSDARG00000039264
mus_musculus	Igfbp5	ENSMUSG00000026185
rattus_norvegicus	Igfbp5	ENSRNOG00000017206

Paralogs (5): IGFBP2 (ENSG00000115457), IGFBP4 (ENSG00000141753), IGFBP3 (ENSG00000146674), IGFBP1 (ENSG00000146678), IGFBP6 (ENSG00000167779)

Protein

Protein identifiers

Insulin-like growth factor-binding protein 5 — P24593 (reviewed: P24593)

All UniProt accessions (2): P24593, C9JXX4

UniProt curated annotations — full annotation on UniProt →

Function. Multifunctional protein that plays a critical role in regulating the availability of IGFs to their receptors and thereby regulates IGF-mediated cellular processes including proliferation, differentiation, and apoptosis in a cell-type specific manner. Increases the cell proliferation of osteoblasts, intestinal smooth muscle cells and neuroblastoma cells. Enhances adhesion and survival of epithelial cells but decreases adhesion of mesenchymal cells. Once secreted, acts as a major mediator of mTORC1-dependent feedback inhibition of IGF1 signaling. Also plays a role in the induction of extracellular matrix (ECM) production and deposition independently of its nuclear translocation and binding to IGFs. Acts itself as a growth factor that can act independently of IGFs to regulate bone formation. Acts as a ligand for the ROR1 receptor which triggers formation of ROR1/HER2 heterodimer to enhance CREB oncogenic signaling.

Subunit / interactions. Interacts with IGF1; this interaction enhances the growth stimulatory effects of IGF1 on fibroblasts. Interacts with CAV1; this interaction allows trafficking of IGFBP5 from the plasma membrane to the nucleus. Interacts with NCL; this interaction is necessary for IGFBP5 localization to the nucleus.

Subcellular location. Secreted. Cytoplasm. Nucleus.

Tissue specificity. Osteosarcoma, and at lower levels in liver, kidney and brain.

Post-translational modifications. Cleaved by C1S in extracellular space.

RefSeq proteins (1): NP_000590* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000716	Thyroglobulin_1	Domain
IPR000867	IGFBP-like	Domain
IPR009030	Growth_fac_rcpt_cys_sf	Homologous_superfamily
IPR012213	IGFBP-5	Family
IPR017891	Insulin_GF-bd_Cys-rich_CS	Conserved_site
IPR022321	IGFBP_1-6_chordata	Family
IPR036857	Thyroglobulin_1_sf	Homologous_superfamily

Pfam: PF00086, PF00219

UniProt features (24 total): disulfide bond 9, helix 3, strand 2, domain 2, signal peptide 1, chain 1, sequence variant 1, turn 1, region of interest 1, compositionally biased region 1, modified residue 1, glycosylation site 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
1H59	X-RAY DIFFRACTION	2.1
7UFG	ELECTRON MICROSCOPY	3.28
1BOE	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P24593-F1	75.91	0.36

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 (1): 116

Disulfide bonds (9): 38–56, 45–59, 67–80, 74–100, 192–219, 230–241, 243–263, 27–53, 30–55

Glycosylation sites (1): 172

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-381426	Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)
R-HSA-8957275	Post-translational protein phosphorylation

MSigDB gene sets: 492 (showing top): GSE45365_NK_CELL_VS_CD8_TCELL_DN, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_MAMMARY_GLAND_MORPHOGENESIS, WANG_CLIM2_TARGETS_UP, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, GOBP_MUSCLE_TISSUE_DEVELOPMENT, GOBP_EPIDERMIS_MORPHOGENESIS, GOBP_GLAND_MORPHOGENESIS, GOBP_NEGATIVE_REGULATION_OF_SMOOTH_MUSCLE_CELL_PROLIFERATION, GOBP_SKELETAL_MUSCLE_ADAPTATION, GCANCTGNY_MYOD_Q6, GOZGIT_ESR1_TARGETS_DN, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN

GO Biological Process (30): regulation of cell growth (GO:0001558), osteoblast differentiation (GO:0001649), signal transduction (GO:0007165), female pregnancy (GO:0007565), cell population proliferation (GO:0008283), negative regulation of smooth muscle cell migration (GO:0014912), negative regulation of translation (GO:0017148), negative regulation of cell migration (GO:0030336), hair follicle morphogenesis (GO:0031069), intracellular signal transduction (GO:0035556), glucose homeostasis (GO:0042593), regulation of insulin-like growth factor receptor signaling pathway (GO:0043567), positive regulation of insulin-like growth factor receptor signaling pathway (GO:0043568), negative regulation of insulin-like growth factor receptor signaling pathway (GO:0043569), type B pancreatic cell proliferation (GO:0044342), negative regulation of osteoblast differentiation (GO:0045668), negative regulation of growth (GO:0045926), insulin-like growth factor receptor signaling pathway (GO:0048009), lung alveolus development (GO:0048286), negative regulation of smooth muscle cell proliferation (GO:0048662), striated muscle cell differentiation (GO:0051146), positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0051897), mammary gland involution (GO:0060056), response to growth hormone (GO:0060416), cellular response to cAMP (GO:0071320), negative regulation of muscle tissue development (GO:1901862), negative regulation of skeletal muscle hypertrophy (GO:1904205), positive regulation of vascular associated smooth muscle cell proliferation (GO:1904707), positive regulation of vascular associated smooth muscle cell migration (GO:1904754), regulation of growth (GO:0040008)

GO Molecular Function (7): fibronectin binding (GO:0001968), insulin-like growth factor I binding (GO:0031994), insulin-like growth factor II binding (GO:0031995), receptor ligand activity (GO:0048018), protein binding (GO:0005515), insulin-like growth factor binding (GO:0005520), growth factor binding (GO:0019838)

GO Cellular Component (7): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), nucleus (GO:0005634), endoplasmic reticulum lumen (GO:0005788), insulin-like growth factor binding protein complex (GO:0016942), insulin-like growth factor ternary complex (GO:0042567), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Metabolism of proteins	1
Post-translational protein modification	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
insulin-like growth factor receptor signaling pathway	3
regulation of growth	2
cellular process	2
intracellular anatomical structure	2
signal transduction	2
regulation of insulin-like growth factor receptor signaling pathway	2
protein binding	2
insulin-like growth factor binding	2
cellular anatomical structure	2
cell growth	1
regulation of cellular component organization	1
ossification	1
cell differentiation	1
cell communication	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
multi-organism reproductive process	1
multi-multicellular organism process	1
smooth muscle cell migration	1
regulation of smooth muscle cell migration	1
negative regulation of cell migration	1
translation	1
regulation of translation	1
negative regulation of gene expression	1
negative regulation of protein metabolic process	1
cell migration	1
regulation of cell migration	1
negative regulation of cell motility	1
hair follicle development	1
anatomical structure morphogenesis	1
hair cycle process	1
epidermis morphogenesis	1
carbohydrate homeostasis	1
regulation of signal transduction	1
positive regulation of signal transduction	1
negative regulation of signal transduction	1
epithelial cell proliferation	1
osteoblast differentiation	1
negative regulation of cell differentiation	1

Protein interactions and networks

STRING

2326 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
IGFBP5	IGF1	P01343	998
IGFBP5	IGF2	P01344	996
IGFBP5	IGFALS	P35858	966
IGFBP5	IGFBP3	P17936	911
IGFBP5	VTN	P01141	831
IGFBP5	FN1	P02751	791
IGFBP5	IGF1R	P08069	788
IGFBP5	PAPPA2	Q9BXP8	784
IGFBP5	FHL2	Q14192	752
IGFBP5	THBS1	P07996	721
IGFBP5	INS	P01308	699
IGFBP5	IL6	P05231	689
IGFBP5	IGFBP7	Q16270	680
IGFBP5	SERPINE1	P05121	636
IGFBP5	PAPPA	Q13219	627

IntAct

243 interactions, top by confidence:

A	B	Type	Score
IGFBP5	CREB3	psi-mi:“MI:0915”(physical association)	0.670
IGFBP5	CLEC17A	psi-mi:“MI:0915”(physical association)	0.600
IGFBP5	SLC38A1	psi-mi:“MI:0915”(physical association)	0.600
IGFBP5	TSPAN12	psi-mi:“MI:0915”(physical association)	0.560
IGFBP5	CLDN9	psi-mi:“MI:0915”(physical association)	0.560
IGFBP5	FCRL3	psi-mi:“MI:0915”(physical association)	0.560
IGFBP5	GJB3	psi-mi:“MI:0915”(physical association)	0.560
IGFBP5	TMX2	psi-mi:“MI:0915”(physical association)	0.560
IGFBP5	AQP6	psi-mi:“MI:0915”(physical association)	0.560
IGFBP5	CLDN20	psi-mi:“MI:0915”(physical association)	0.560
IGFBP5	GPR42	psi-mi:“MI:0915”(physical association)	0.560
IGFBP5	HSD17B13	psi-mi:“MI:0915”(physical association)	0.560
IGFBP5	ANKS6	psi-mi:“MI:0915”(physical association)	0.560
IGFBP5	TMEM45A	psi-mi:“MI:0915”(physical association)	0.560
IGFBP5	LAPTM4B	psi-mi:“MI:0915”(physical association)	0.560
IGFBP5	LAYN	psi-mi:“MI:0915”(physical association)	0.560
IGFBP5	MFF	psi-mi:“MI:0915”(physical association)	0.560
IGFBP5	LDLRAD1	psi-mi:“MI:0915”(physical association)	0.560
IGFBP5	SYNE4	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (127): IGFBP5 (Reconstituted Complex), CREB3 (Two-hybrid), IGFBP5 (Two-hybrid), IGFBP5 (Two-hybrid), IGFBP5 (Two-hybrid), BAG6 (Two-hybrid), IGFBP5 (Two-hybrid), IGFBP5 (Two-hybrid), IGFBP5 (Two-hybrid), IGFBP5 (Two-hybrid), IGFBP5 (Two-hybrid), IGFBP5 (Two-hybrid), IGFBP5 (Two-hybrid), IGFBP5 (Two-hybrid), IGFBP5 (Two-hybrid)

ESM2 similar proteins: A4IIA2, A5A8Y8, B3F211, P01186, P08833, P10769, P12843, P13384, P15473, P16042, P16229, P17936, P18065, P19336, P21743, P21744, P24591, P24592, P24593, P24594, P24787, P24853, P35455, P35572, P47876, P47877, P47878, P47879, P47880, P49705, P51693, P97466, Q03157, Q05717, Q05718, Q07079, Q13253, Q28985, Q29400, Q32L50

Diamond homologs: A4IIA2, A5PKD8, B3F211, D3ZKF5, E1BJW1, P08833, P12843, P13384, P15473, P16611, P17936, P18065, P20959, P21743, P21744, P22692, P24591, P24592, P24593, P24594, P24853, P24854, P35572, P42642, P47876, P47877, P47878, P47879, P47880, P49705, Q05716, Q05717, Q05718, Q07079, Q16270, Q28893, Q28985, Q29400, Q5XHC5, Q61581

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
“MYOD1/SWI/SNF complex”	“up-regulates quantity by expression”	IGFBP5	“transcriptional regulation”
mir-143	“down-regulates quantity”	IGFBP5	“post transcriptional regulation”
IGFBP5	“up-regulates activity”	Skeletal_muscle_differentiation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 79 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
Tight junction interactions	5	41.9×	2e-05
Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)	5	9.8×	7e-03
Transport of small molecules	8	4.6×	1e-02

GO biological processes:

GO term	Partners	Fold	FDR
calcium-independent cell-cell adhesion	5	59.9×	8e-06
bicellular tight junction assembly	5	24.7×	4e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	29
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

981 predictions. Top by Δscore:

Variant	Effect	Δscore
2:216676757:A:AC	donor_gain	1.0000
2:216676758:A:C	donor_gain	1.0000
2:216678107:CGTA:C	donor_loss	1.0000
2:216678108:GTACC:G	donor_loss	1.0000
2:216678109:TA:T	donor_loss	1.0000
2:216678111:C:A	donor_loss	1.0000
2:216678111:CCTG:C	donor_gain	1.0000
2:216678845:TGCAC:T	donor_loss	1.0000
2:216678846:GCAC:G	donor_loss	1.0000
2:216678847:CACCT:C	donor_loss	1.0000
2:216678848:ACC:A	donor_loss	1.0000
2:216678849:C:CG	donor_loss	1.0000
2:216678856:AGACT:A	donor_gain	1.0000
2:216678861:C:CA	donor_gain	1.0000
2:216678870:T:C	donor_gain	1.0000
2:216678927:TGG:T	donor_gain	1.0000
2:216679076:CTCT:C	acceptor_gain	1.0000
2:216679077:TCTC:T	acceptor_loss	1.0000
2:216679080:C:CC	acceptor_gain	1.0000
2:216679080:C:T	acceptor_loss	1.0000
2:216676753:A:AC	donor_gain	0.9900
2:216676754:C:CC	donor_gain	0.9900
2:216676759:CGTTG:C	donor_gain	0.9900
2:216676879:TGCA:T	acceptor_gain	0.9900
2:216676881:CA:C	acceptor_gain	0.9900
2:216676882:ACTGG:A	acceptor_loss	0.9900
2:216676883:C:CC	acceptor_gain	0.9900
2:216676883:C:CG	acceptor_loss	0.9900
2:216676884:T:C	acceptor_loss	0.9900
2:216678230:CC:C	acceptor_gain	0.9900

AlphaMissense

1778 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:216676827:C:A	G248V	1.000
2:216676827:C:T	G248E	1.000
2:216676828:C:A	G248W	1.000
2:216676842:C:G	C243S	1.000
2:216676843:A:G	C243R	1.000
2:216676843:A:T	C243S	1.000
2:216676844:C:A	W242C	1.000
2:216676844:C:G	W242C	1.000
2:216676846:A:G	W242R	1.000
2:216676846:A:T	W242R	1.000
2:216676847:G:C	C241W	1.000
2:216676848:C:A	C241F	1.000
2:216676848:C:G	C241S	1.000
2:216676848:C:T	C241Y	1.000
2:216676849:A:G	C241R	1.000
2:216676849:A:T	C241S	1.000
2:216676854:C:T	G239D	1.000
2:216676855:C:A	G239C	1.000
2:216676855:C:G	G239R	1.000
2:216676880:G:C	C230W	1.000
2:216676881:C:G	C230S	1.000
2:216676881:C:T	C230Y	1.000
2:216676882:A:G	C230R	1.000
2:216676882:A:T	C230S	1.000
2:216678112:C:A	Q229H	1.000
2:216678112:C:G	Q229H	1.000
2:216678115:C:A	K228N	1.000
2:216678115:C:G	K228N	1.000
2:216678126:A:C	Y225D	1.000
2:216678131:C:A	G223V	1.000

dbSNP variants (sampled 300 via entrez): RS1000002503 (2:216682757 G>A), RS1000191345 (2:216678284 G>A,C), RS1000194504 (2:216694821 A>G), RS1000308028 (2:216695193 C>G), RS1000403432 (2:216683216 G>A), RS1000460479 (2:216688790 C>T), RS1000535963 (2:216690334 C>G), RS1000799679 (2:216696229 C>T), RS1001049994 (2:216673802 C>T), RS1001196256 (2:216687486 T>C), RS1001475366 (2:216685088 C>T), RS1001517878 (2:216687812 C>T), RS1001590396 (2:216691723 T>G), RS1001776542 (2:216675614 T>C), RS1001811412 (2:216684714 A>G)

Disease associations

OMIM: gene MIM:146734 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

24 associations (top):

Study	Trait	p-value
GCST001525_7	Visceral fat	1.000000e-07
GCST001856_26	Thyroid hormone levels	2.000000e-07
GCST001856_35	Thyroid hormone levels	3.000000e-15
GCST001856_56	Thyroid hormone levels	8.000000e-11
GCST002707_4	Serum thyroid-stimulating hormone levels	4.000000e-06
GCST003094_2	Mitral valve prolapse	3.000000e-11
GCST003401_6	Glomerular filtration rate in non diabetics (creatinine)	1.000000e-10
GCST003790_27	Glomerular filtration rate	8.000000e-07
GCST003988_20	Hypothyroidism	6.000000e-09
GCST004988_36	Breast cancer	3.000000e-41
GCST004988_37	Breast cancer	1.000000e-95
GCST005984_27	Glomerular filtration rate	1.000000e-09
GCST005985_63	Creatinine levels	4.000000e-09
GCST006585_1730	Blood protein levels	7.000000e-10
GCST007096_6	Pulse pressure	5.000000e-08
GCST007344_60	Estimated glomerular filtration rate	9.000000e-14
GCST007431_38	Lung function (FEV1/FVC)	1.000000e-14
GCST007432_9	FEV1	2.000000e-10
GCST008839_204	Height	5.000000e-07
GCST009391_1677	Metabolite levels	5.000000e-06
GCST009391_2044	Metabolite levels	2.000000e-06
GCST009391_530	Metabolite levels	3.000000e-08
GCST009391_741	Metabolite levels	9.000000e-06
GCST010653_62	Thyroid stimulating hormone levels	3.000000e-78

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0004730	hormone measurement
EFO:0005763	pulse pressure measurement
EFO:0004713	FEV/FVC ratio
EFO:0004314	forced expiratory volume
EFO:0010342	cholesteryl ester 16:1 measurement
EFO:0010508	malate measurement
EFO:0010528	quinolinic acid measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2665 (SINGLE PROTEIN)

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

ChEMBL bioactivities

10 potent at pChembl≥5 of 11 total, top 10 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.28	Ki	5.2	nM	CHEMBL292700
8.25	Ki	5.6	nM	CHEMBL292700
8.14	Ki	7.2	nM	CHEMBL58396
7.89	Ki	13	nM	CHEMBL56978
7.68	Ki	20.95	nM	CHEMBL130994
7.28	Ki	53	nM	CHEMBL60797
7.28	Ki	52	nM	CHEMBL299259
6.96	Ki	110	nM	CHEMBL292347
6.62	Ki	240	nM	CHEMBL299912
5.28	Ki	5300	nM	CHEMBL61196

PubChem BioAssay actives

10 with measured affinity, of 37 total; 9 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
1-(3,4-dihydroxybenzoyl)-6,7-dihydroxyisoquinoline-3-carboxylic acid	93354: The compound was tested for binding affinity against Insulin-like growth factor binding protein 5	ki	0.0052	uM
1-[(3,4-dihydroxyphenyl)methyl]-6,7-dihydroxyisoquinoline-3-carboxylic acid	93353: Ability of compound to displace Insulin-Like Growth Factor (IGF-I) from its binding to Insulin-like growth factor binding protein 5 (IGFBP-5)	ki	0.0072	uM
4-[(3,4-dihydroxyphenyl)methyl]-6,7-dihydroxyquinoline-2-carboxylic acid	93353: Ability of compound to displace Insulin-Like Growth Factor (IGF-I) from its binding to Insulin-like growth factor binding protein 5 (IGFBP-5)	ki	0.0130	uM
1-(3,4-dihydroxybenzoyl)-6,7-dihydroxy-2H-isoquinolin-3-one	93354: The compound was tested for binding affinity against Insulin-like growth factor binding protein 5	ki	0.0209	uM
7-amino-4-[(3,4-dihydroxyphenyl)methyl]-6-hydroxyquinoline-2-carboxylic acid	93353: Ability of compound to displace Insulin-Like Growth Factor (IGF-I) from its binding to Insulin-like growth factor binding protein 5 (IGFBP-5)	ki	0.0520	uM
4-[(3,4-dihydroxyphenyl)methyl]-7-fluoro-6-hydroxyquinoline-2-carboxylic acid	93353: Ability of compound to displace Insulin-Like Growth Factor (IGF-I) from its binding to Insulin-like growth factor binding protein 5 (IGFBP-5)	ki	0.0530	uM
4-[(3,4-dihydroxyphenyl)methyl]-6-hydroxyquinoline-2,7-dicarboxylic acid	93353: Ability of compound to displace Insulin-Like Growth Factor (IGF-I) from its binding to Insulin-like growth factor binding protein 5 (IGFBP-5)	ki	0.1100	uM
7-chloro-4-[(3,4-dihydroxyphenyl)methyl]-6-hydroxyquinoline-2-carboxylic acid	93353: Ability of compound to displace Insulin-Like Growth Factor (IGF-I) from its binding to Insulin-like growth factor binding protein 5 (IGFBP-5)	ki	0.2400	uM
7-amino-4-[(3,4-dihydroxyphenyl)methyl]-6-methoxyquinoline-2-carboxylic acid	93353: Ability of compound to displace Insulin-Like Growth Factor (IGF-I) from its binding to Insulin-like growth factor binding protein 5 (IGFBP-5)	ki	5.3000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Estradiol	affects expression, affects cotreatment, decreases expression, increases expression, decreases reaction	8
sodium arsenite	affects cotreatment, increases abundance, increases methylation, decreases expression	5
Valproic Acid	affects expression, decreases expression, decreases methylation, increases expression	4
trichostatin A	affects cotreatment, decreases expression, increases expression	3
Progesterone	affects cotreatment, decreases expression	3
Tetrachlorodibenzodioxin	affects cotreatment, increases expression, affects expression	3
Tretinoin	affects cotreatment, decreases expression	3
bisphenol F	decreases expression, increases expression	2
bisphenol A	affects expression, decreases expression	2
entinostat	decreases expression, affects cotreatment	2
monomethylarsonous acid	decreases expression, decreases reaction, increases expression	2
(+)-JQ1 compound	decreases expression	2
Resveratrol	affects cotreatment, decreases expression	2
Arsenic	decreases expression, increases abundance, affects cotreatment	2
Cisplatin	decreases expression, affects response to substance	2
Dexamethasone	increases expression, affects cotreatment	2
Doxorubicin	decreases expression, increases expression	2
Folic Acid	affects cotreatment, increases expression, affects expression	2
Hydrogen Peroxide	increases expression	2
Smoke	decreases expression, increases abundance, increases expression	2
Tamoxifen	increases response to substance, affects expression	2
Tobacco Smoke Pollution	affects expression, decreases expression	2
8-Bromo Cyclic Adenosine Monophosphate	increases expression	2
Thapsigargin	decreases expression, increases expression	2
p-Chloromercuribenzoic Acid	affects cotreatment, decreases expression	2
aristolochic acid I	decreases expression	1
methylmercuric chloride	decreases expression	1
sodium arsenate	decreases expression, increases abundance	1
IMOL S-140	increases expression	1
arsenite	decreases expression, decreases reaction, increases expression	1

ChEMBL screening assays

24 unique, capped per target: 24 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL697415	Binding	Dissociation constant in binding to Insulin-like growth factor binding protein 5 at the residue R87	In silico and NMR identification of inhibitors of the IGF-I and IGF-binding protein-5 interaction. — J Med Chem

Clinical trials (associated diseases)

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