Details for: IGFBP6

Gene ID: 3489

Gene Type:  Protein-coding  - A gene that serves as a template for producing a messenger RNA (mRNA) molecule, which is then translated into a functional protein.

Symbol: IGFBP6

Ensembl ID: ENSG00000167779

Description: insulin like growth factor binding protein 6

Selected Context(s):  Overall

Cell Significance Landscape

Contexts:

Associated with

  • Metabolism of proteins
    (R-HSA-392499)
  • Regulation of insulin-like growth factor (igf) transport and uptake by insulin-like growth factor binding proteins (igfbps)
    (R-HSA-381426)
  • Cell migration
    (GO:0016477)
  • Extracellular region
    (GO:0005576)
  • Extracellular space
    (GO:0005615)
  • Fibronectin binding
    (GO:0001968)
  • Identical protein binding
    (GO:0042802)
  • Insulin-like growth factor binary complex
    (GO:0042568)
  • Insulin-like growth factor i binding
    (GO:0031994)
  • Insulin-like growth factor ii binding
    (GO:0031995)
  • Negative regulation of canonical wnt signaling pathway
    (GO:0090090)
  • Negative regulation of cell population proliferation
    (GO:0008285)
  • Positive regulation of mapk cascade
    (GO:0043410)
  • Positive regulation of stress-activated mapk cascade
    (GO:0032874)
  • Protein binding
    (GO:0005515)
  • Regulation of insulin-like growth factor receptor signaling pathway
    (GO:0043567)
  • Signaling receptor binding
    (GO:0005102)
  • Signal transduction
    (GO:0007165)

Significant Cells

Cell Significance Index (CSI) scores for the chosen context(s)

  • alveolar adventitial fibroblast CL4028006
    CSI 23.33
    rCSI 36.85%
    PRS 95.11
  • adventitial cell CL0002503
    CSI 20.87
    rCSI 49.85%
    PRS 96.02
  • keratocyte CL0002363
    CSI 18.58
    rCSI 44.66%
    PRS 94.78
  • skin fibroblast CL0002620
    CSI 12.91
    rCSI 11.13%
    PRS 93.82
  • microcirculation associated smooth muscle cell CL0008035
    CSI 10.51
    rCSI 30.43%
    PRS 93.7
  • tendon cell CL0000388
    CSI 10.24
    rCSI 26.61%
    PRS 96.02
  • respiratory hillock cell CL4030023
    CSI 8.94
    rCSI 15.93%
    PRS 96.29
  • fibroblast of lung CL0002553
    CSI 7.88
    rCSI 7.33%
    PRS 95.36
  • stromal cell CL0000499
    CSI 7.41
    rCSI 20.85%
    PRS 91.42
  • bronchus fibroblast of lung CL2000093
    CSI 6.95
    rCSI 5.65%
    PRS 93.99
  • stem cell CL0000034
    CSI 6.8
    rCSI 6.55%
    PRS 91.66
  • myofibroblast cell CL0000186
    CSI 6.73
    rCSI 9.31%
    PRS 91.93
  • pancreatic stellate cell CL0002410
    CSI 5.83
    rCSI 33.94%
    PRS 95.33
  • stromal cell of ovary CL0002132
    CSI 5.51
    rCSI 15.15%
    PRS 96.1
  • perivascular cell CL4033054
    CSI 5.3
    rCSI 7.25%
    PRS 96.45
  • basal-myoepithelial cell of mammary gland CL0002324
    CSI 5.11
    rCSI 9.66%
    PRS 97.4
  • mesenchymal stem cell of adipose tissue CL0002570
    CSI 4.99
    rCSI 27.85%
    PRS 95.52
  • fibroblast of breast CL4006000
    CSI 4.67
    rCSI 19.64%
    PRS 95.99
  • respiratory basal cell CL0002633
    CSI 4.24
    rCSI 4.4%
    PRS 95.37
  • smooth muscle cell CL0000192
    CSI 4.15
    rCSI 9.9%
    PRS 89.99
  • alveolar type 1 fibroblast cell CL4028004
    CSI 4.12
    rCSI 4.51%
    PRS 95.54
  • fibroblast CL0000057
    CSI 4.01
    rCSI 11.54%
    PRS 86.18
  • myoepithelial cell CL0000185
    CSI 3.78
    rCSI 9.55%
    PRS 95.65
  • lung pericyte CL0009089
    CSI 3.69
    rCSI 9.73%
    PRS 96.8
  • basal cell CL0000646
    CSI 3.58
    rCSI 4.78%
    PRS 91.89
  • early lymphoid progenitor CL0000936
    CSI 3.41
    rCSI 2.99%
    PRS 96.43
  • blood vessel endothelial cell CL0000071
    CSI 3.37
    rCSI 7%
    PRS 93.03
  • vascular associated smooth muscle cell CL0000359
    CSI 3.23
    rCSI 10.46%
    PRS 93.06
  • epithelial cell of lung CL0000082
    CSI 3.14
    rCSI 2.6%
    PRS 95.17
  • vascular leptomeningeal cell CL4023051
    CSI 3.03
    rCSI 5.32%
    PRS 92.2
  • adipocyte CL0000136
    CSI 2.98
    rCSI 3.83%
    PRS 87.89
  • ependymal cell CL0000065
    CSI 2.97
    rCSI 6.04%
    PRS 80.08
  • epithelial cell of lower respiratory tract CL0002632
    CSI 2.95
    rCSI 2.28%
    PRS 95.89
  • mesodermal cell CL0000222
    CSI 2.93
    rCSI 3.52%
    PRS 93.66
  • muscle cell CL0000187
    CSI 2.82
    rCSI 5.8%
    PRS 95.45
  • respiratory suprabasal cell CL4033048
    CSI 2.73
    rCSI 3.51%
    PRS 95.23
  • granulocyte CL0000094
    CSI 2.7
    rCSI 4.12%
    PRS 96.77
  • epithelial cell of proximal tubule CL0002306
    CSI 2.57
    rCSI 6.28%
    PRS 89.39
  • tracheobronchial smooth muscle cell CL0019019
    CSI 2.54
    rCSI 4.48%
    PRS 96.08
  • club cell CL0000158
    CSI 2.47
    rCSI 3.61%
    PRS 91.17
  • hepatic stellate cell CL0000632
    CSI 2.45
    rCSI 9.19%
    PRS 91.63
  • mononuclear phagocyte CL0000113
    CSI 2.32
    rCSI 5.11%
    PRS 96.16
  • smooth muscle cell of prostate CL1000487
    CSI 2.22
    rCSI 13.04%
    PRS 96.25
  • conjunctival epithelial cell CL1000432
    CSI 2.07
    rCSI 3.17%
    PRS 93.34
  • corneal epithelial cell CL0000575
    CSI 1.84
    rCSI 5.27%
    PRS 94.95
  • pancreatic ductal cell CL0002079
    CSI 1.84
    rCSI 3.58%
    PRS 95.01
  • odontoblast CL0000060
    CSI 1.79
    rCSI 40.43%
    PRS 97.2
  • uterine smooth muscle cell CL0002601
    CSI 1.77
    rCSI 11.64%
    PRS 96.19
  • chondrocyte CL0000138
    CSI 1.7
    rCSI 2.71%
    PRS 91.07
  • basal cell of prostate epithelium CL0002341
    CSI 1.53
    rCSI 4.41%
    PRS 95.69
  • kidney loop of Henle thin ascending limb epithelial cell CL1001107
    CSI 1.5
    rCSI 3.89%
    PRS 92.65
  • blood vessel smooth muscle cell CL0019018
    CSI 1.49
    rCSI 12.1%
    PRS 93.22
  • mesenchymal cell CL0008019
    CSI 1.26
    rCSI 3.21%
    PRS 90.98
  • endothelial cell of uterus CL0009095
    CSI 1.2
    rCSI 8.75%
    PRS 97.34
  • endothelial cell of arteriole CL1000412
    CSI 1.19
    rCSI 6.57%
    PRS 97.51
  • bronchiolar smooth muscle cell CL4033017
    CSI 0.93
    rCSI 14%
    PRS 96.89
  • brain vascular cell CL4023072
    CSI 0.9
    rCSI 9.28%
    PRS 89.59
  • enteroglial cell CL4040002
    CSI 0.86
    rCSI 4.49%
    PRS 94.29
  • mesenchymal stem cell CL0000134
    CSI 0.85
    rCSI 9.26%
    PRS 95.63
  • kidney loop of Henle thick ascending limb epithelial cell CL1001106
    CSI 0.76
    rCSI 6.58%
    PRS 90.07
  • pulmonary alveolar type 1 cell CL0002062
    CSI 0.61
    rCSI 3.51%
    PRS 92.09
  • kidney interstitial cell CL1000500
    CSI 0.59
    rCSI 9.75%
    PRS 96.17
  • epithelial cell of esophagus CL0002252
    CSI 0.53
    rCSI 5.26%
    PRS 92.24
  • prostate gland microvascular endothelial cell CL2000059
    CSI 0.29
    rCSI 6.83%
    PRS 96.23

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this specific cell.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.
Network Configuration

Explore relationships of the current gene. Select an Interaction Source: 'ONTOLOGY' for shared pathways (GO/Reactome) or 'STRING' for protein-protein interactions. Further refine by selecting context genes and comparing Cell Significance Index (CSI) scores between baseline and target cell types and their specific contexts.

Comma-separated if multiple.
Comma-separated if multiple.
Legend:
  • Query Gene
  • Node Color (Target Cell CSI, relative to current network):
    • Very High
    • High
    • Medium
    • Low
    • Very Low
    • CSI N/A
  • Node Size: Proportional to Target Cell CSI magnitude
  • STRING PPI Edge
  • Shared Pathway Edge (ONTOLOGY)

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Other Information

This section provides additional information about the gene, including a description generated by an AI language model and details about associated proteins.

## Summary Insulin-like growth factor-binding protein 6, encoded by the [IGFBP6](/details-gene/3489) gene, is a secreted protein belonging to the IGFBP family, which are critical regulators of insulin-like growth factor (IGF) activity. It exhibits a high binding affinity for IGF-II, thereby modulating its bioavailability and interaction with cell surface receptors ([Link](https://pubmed.ncbi.nlm.nih.gov/2551732/)). **Overall**, expression data reveals that [IGFBP6](/details-gene/3489) is a prominent marker for various mesenchymal and stromal cell lineages, particularly fibroblasts. Its significant expression in cells such as [alveolar adventitial fibroblast](/details-cell/CL4028006), [adventitial cell](/details-cell/CL0002503), and [keratocyte](/details-cell/CL0002363) suggests a fundamental role in tissue structure, homeostasis, and repair by controlling local growth factor signaling in the extracellular matrix. Its function is associated with clinical relevance through OMIM entry [146735](https://omim.org/entry/146735). ## Cellular Roles and Expression Landscape The expression profile of [IGFBP6](/details-gene/3489) firmly establishes it as a key component of the secretome of stromal and mesenchymal cells across various tissues. **Overall**, the gene shows the highest significance in fibroblast populations, including [alveolar adventitial fibroblast](/details-cell/CL4028006) (CSI: 23.33), [skin fibroblast](/details-cell/CL0002620) (CSI: 12.91), and [fibroblast of lung](/details-cell/CL0002553) (CSI: 7.88). This pattern is further supported by high significance in functionally related cells such as [adventitial cell](/details-cell/CL0002503) (CSI: 20.87), [keratocyte](/details-cell/CL0002363) (CSI: 18.58) in the cornea, [tendon cell](/details-cell/CL0000388) (CSI: 10.24), and [myofibroblast cell](/details-cell/CL0000186) (CSI: 6.73). This consistent, high-level expression across diverse connective tissue cells highlights its role in maintaining tissue architecture and mediating intercellular communication within the tissue stroma. Its presence in [stem cell](/details-cell/CL0000034) populations (CSI: 6.80) and [pancreatic stellate cell](/details-cell/CL0002410) (CSI: 5.83) further suggests a role in tissue regeneration, differentiation, and the pathological remodeling seen in fibrotic conditions. The collective data indicate that [IGFBP6](/details-gene/3489) is a crucial regulator of the microenvironment in tissues rich in connective and structural cells. ## Pathways and Molecular Function Functionally, [IGFBP6](/details-gene/3489) operates primarily in the [extracellular space](/details-cell/GO:0005615) as a modulator of growth factor signaling. Its principal molecular function is the high-affinity binding of [insulin-like growth factor ii](/details-cell/GO:0031995) and, to a lesser extent, [insulin-like growth factor i](/details-cell/GO:0031994), as established in early purification studies ([Link](https://doi.org/10.1016/s0021-9258(19)39711-x), [Link](https://doi.org/10.1016/0014-5793(89)81101-9)). This activity is central to the Reactome pathway for the '[Regulation of insulin-like growth factor (igf) transport and uptake by insulin-like growth factor binding proteins (igfbps)](https://reactome.org/content/detail/R-HSA-381426)', where it sequesters IGFs to prevent their binding to receptors. Beyond its canonical role in IGF signaling, [IGFBP6](/details-gene/3489) is implicated in broader signaling networks. Gene Ontology annotations indicate its involvement in the [negative regulation of canonical wnt signaling pathway](/details-cell/GO:0090090) and both the [positive regulation of mapk cascade](/details-cell/GO:0043410) and [stress-activated mapk cascade](/details-cell/GO:0032874). These functions are consistent with its roles in controlling [cell migration](/details-cell/GO:0016477) and the [negative regulation of cell population proliferation](/details-cell/GO:0008285), processes that are fundamental to the behavior of fibroblasts and stromal cells during development, wound healing, and disease. ## Research Directions The specific and high-level expression of [IGFBP6](/details-gene/3489) in fibroblast and stromal cell populations, coupled with its function as a key modulator of the extracellular signaling environment, opens several avenues for future investigation. **Proposed Hypotheses:** 1. Given its high expression in multiple fibroblast types and its role in regulating cell proliferation, [IGFBP6](/details-gene/3489) may function as a crucial brake on fibrotic processes. Downregulation of [IGFBP6](/details-gene/3489) in the tissue microenvironment could unleash IGF-mediated fibroblast activation and proliferation, driving the pathology of diseases such as idiopathic pulmonary fibrosis or scleroderma. 2. The involvement of [IGFBP6](/details-gene/3489) in the negative regulation of Wnt signaling suggests a tumor-suppressive role within the stromal compartment. It may act to maintain homeostasis and suppress epithelial tumorigenesis by limiting pro-proliferative Wnt signals, and its loss in the tumor microenvironment could be a permissive event for cancer progression. 3. The protein's role in regulating cell migration and MAPK signaling suggests it is an important orchestrator of the wound healing response. It may be dynamically regulated following tissue injury to control the migration and activation of fibroblasts to the wound site, with improper expression leading to impaired healing or scar formation. **Experimental Approach:** To test the hypothesis that [IGFBP6](/details-gene/3489) acts as an anti-fibrotic factor (Hypothesis 1), a compelling experiment would involve a murine model of lung fibrosis. `Igfbp6` knockout mice and wild-type controls would be subjected to bleomycin-induced lung injury. The severity of fibrosis would be assessed at multiple time points post-injury by quantifying collagen deposition using hydroxyproline assays and Masson's trichrome staining of lung sections. Furthermore, lung fibroblasts would be isolated from both genotypes to assess differences in proliferative capacity, migratory potential, and expression of fibrotic markers (e.g., Acta2, Col1a1) in response to stimulation with growth factors like IGF-II or TGF-beta *in vitro*. **Therapeutic Potential:** As a secreted, extracellular protein, [IGFBP6](/details-gene/3489) has significant therapeutic potential. For conditions characterized by excessive fibroblast activity, such as organ fibrosis or hypertrophic scarring, recombinant human [IGFBP6](/details-gene/3489) could be developed as a biologic therapeutic. Administration of the protein would be a strategy of activation or supplementation, aimed at sequestering pro-fibrotic IGFs and restoring homeostatic control over stromal cell behavior. Conversely, if it is found to inhibit desired regenerative processes, targeting it for inhibition with neutralizing antibodies could be a viable strategy. Its specific expression pattern in stromal, rather than epithelial, compartments suggests that such a therapy could have a favorable side-effect profile.

Genular Protein ID: 2923364751

Symbol: IBP6_HUMAN

Name: N/A

UniProtKB Accession Codes:

P24592 Q14492

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 Bgee 1 BindingDB 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 1 CDD 1 CTD 1 ChEMBL 1 ChiTaRS 1 DMDM 1 DNASU 1 DisGeNET 1 DrugBank 1 EMBL 8 Ensembl 1 EvolutionaryTrace 1 ExpressionAtlas 1 GO 15 Gene3D 2 GeneCards 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 GlyConnect 1 GlyCosmos 1 GlyGen 1 HGNC 1 HPA 1 InParanoid 1 IntAct 1 InterPro 6 KEGG 1 MANE-Select 1 MEROPS 1 MIM 1 MINT 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 OrthoDB 1 PANTHER 2 PDB 2 PDBsum 2 PIR 2 PRINTS 2 PRO 1 PROSITE 3 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 1 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 1 RNAct 1 Reactome 1 RefSeq 1 SMART 2 SMR 1 STRING 1 SUPFAM 2 SignaLink 1 SwissPalm 1 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 jPOST 1 neXtProt 1

Citations:

PubMed ID: 1709161

Title: Identification and molecular cloning of two new 30-kDa insulin-like growth factor binding proteins isolated from adult human serum.

PubMed ID: 1709161

DOI: 10.1016/s0021-9258(18)31549-7

PubMed ID: 10087296

Title: Characterization and chromosomal localization of the human insulin-like growth factor-binding protein 6 gene.

PubMed ID: 10087296

DOI: 10.1007/s003359901005

PubMed ID: 15489334

Title: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).

PubMed ID: 15489334

DOI: 10.1101/gr.2596504

PubMed ID: 1719383

Title: Isolation and molecular cloning of insulin-like growth factor-binding protein-6.

PubMed ID: 1719383

DOI: 10.1210/mend-5-7-938

PubMed ID: 1697583

Title: Isolation from adult human serum of four insulin-like growth factor (IGF) binding proteins and molecular cloning of one of them that is increased by IGF I administration and in extrapancreatic tumor hypoglycemia.

PubMed ID: 1697583

DOI: 10.1016/s0021-9258(18)77200-1

PubMed ID: 2551732

Title: Isolation from human cerebrospinal fluid of a new insulin-like growth factor-binding protein with a selective affinity for IGF-II.

PubMed ID: 2551732

DOI: 10.1016/0014-5793(89)81101-9

PubMed ID: 2154495

Title: Purification and properties of a novel insulin-like growth factor-II binding protein from transformed human fibroblasts.

PubMed ID: 2154495

DOI: 10.1016/s0021-9258(19)39711-x

PubMed ID: 1850257

Title: A novel human insulin-like growth factor binding protein secreted by osteoblast-like cells.

PubMed ID: 1850257

DOI: 10.1016/0006-291x(91)90911-p

PubMed ID: 9572875

Title: Identification of O-glycosylation sites and partial characterization of carbohydrate structure and disulfide linkages of human insulin-like growth factor binding protein 6.

PubMed ID: 9572875

DOI: 10.1021/bi972894e

PubMed ID: 10329650

Title: The N-terminal disulfide linkages of human insulin-like growth factor-binding protein-6 (hIGFBP-6) and hIGFBP-1 are different as determined by mass spectrometry.

PubMed ID: 10329650

DOI: 10.1074/jbc.274.21.14587

PubMed ID: 19838169

Title: Enrichment of glycopeptides for glycan structure and attachment site identification.

PubMed ID: 19838169

DOI: 10.1038/nmeth.1392

PubMed ID: 24003225

Title: Prohibitin-2 binding modulates insulin-like growth factor-binding protein-6 (IGFBP-6)-induced rhabdomyosarcoma cell migration.

PubMed ID: 24003225

DOI: 10.1074/jbc.m113.510826

Sequence Information:

  • Length: 240
  • Mass: 25322
  • Checksum: 285308231C025009
  • Sequence:
    • MTPHRLLPPL LLLLALLLAA SPGGALARCP GCGQGVQAGC PGGCVEEEDG GSPAEGCAEA 
EGCLRREGQE CGVYTPNCAP GLQCHPPKDD EAPLRALLLG RGRCLPARAP AVAEENPKES 
KPQAGTARPQ DVNRRDQQRN PGTSTTPSQP NSAGVQDTEM GPCRRHLDSV LQQLQTEVYR 
GAQTLYVPNC DHRGFYRKRQ CRSSQGQRRG PCWCVDRMGK SLPGSPDGNG SSSCPTGSSG