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IGFBP6 (insulin-like growth factor binding protein 6)

Written2014-04Leon A Bach
Department of Endocrinology, Diabetes, Alfred Hospital, Department of Medicine (Alfred), Monash University, Melbourne 3004, Australia

(Note : for Links provided by Atlas : click)

Identity

Alias_namesinsulin-like growth factor binding protein 6
HGNC (Hugo) IGFBP6
LocusID (NCBI) 3489
Atlas_Id 40933
Location 12q13.13  [Link to chromosome band 12q13]
Location_base_pair Starts at 53491436 and ends at 53496128 bp from pter ( according to hg19-Feb_2009)  [Mapping IGFBP6.png]
Fusion genes
(updated 2016)
ALG10B (12q12) / IGFBP6 (12q13.13)

DNA/RNA

Description The size of the IGFBP6 gene is 4.91 kb and it contains 4 exons (Thierry-Mieg and Thierry-Mieg, 2006).
Transcription One 1175 bp transcript encodes the full-sized 240 amino acid protein. Smaller transcripts sized 597, 705 and 463 bp may be incomplete and putatively encode fragments containing 51-140 amino acids (Thierry-Mieg and Thierry-Mieg, 2006).

Protein

 
  Structure of the C-terminal domain of human IGFBP-6 (Headey et al., 2004; Bach et al., 2013).
Description IGFBP-6 belongs to the insulin-like growth factor binding protein family. It is expressed as a 240 amino acid proprotein, and processed to a 213-216 amino acid mature protein. It consists of 3 domains: the N- and C-terminal domains, which contain internal disulfide bonds, are joined by a linker domain. It contains 8 disulfide bonds, 5 in the N-terminal IGFBP domain and 3 in the C-terminal domain (Neumann et al., 1998; Neumann and Bach, 1999). Of these, the first 3 N-terminal disulfides are unique, whereas the remaining 2 N-terminal and 3 C-terminal disulfides are homologous with other IGFBPs. A peptide based on the N-terminal subdomain is largely unstructured (Chandrashekaran et al., 2007), whereas the IGF binding subdomain is conserved with other IGFBPs. Human IGFBP-6 is O-glycosylated on 5 Ser/Thr residues within the linker domain, which has a distinct sequence from other IGFBPs (Bach et al., 1992; Neumann et al., 1998). The C-terminal domain contains a thyroglobulin type 1 fold (Headey et al., 2004), which is also true for other IGFBPs, and a functional nuclear localization sequence (Iosef et al., 2008).
Expression IGFBP6 is widely expressed in human tissues, with low levels of transcripts found in most tissues. Expression is highest in smooth muscle, olfactory bulb, ganglia, retina and the atrioventricular node (Wu et al., 2013). IGFBP6 is also found in many body fluids, including serum, cerebrospinal fluid, amniotic fluid, and follicular fluid (Baxter and Saunders, 1992; Bach, 1999; Kolker et al., 2012). IGFBP6 expression is regulated in a cell-specific manner by cAMP, IGFs, retinoic acid, vitamin D, glucocorticoids, p53, beta-catenin, hedgehog, TGF-beta and SEMA3B (Bach et al., 2013).
Localisation Predominantly extracellular. Nuclear localization via a C-domain nuclear localization signal that binds importin-a has also been reported (Iosef et al., 2008).
Function Unlike other IGFBPs, IGFBP-6 has a ~50-fold binding preference for IGF-II over IGF-I. It therefore is a relatively specific inhibitor of IGF-II actions (Bach, 1999; Bach, 2005; Bach et al., 2013). It is antiproliferative and proapoptotic in a number of cell lines in vitro (Bach, 1999; Bach, 2005; Bach et al., 2013). At least some of its actions in regulating cell fate are mediated by interaction with Ku80, a DNA-end binding protein (Iosef et al., 2010). IGFBP-6 has also been reported to have IGF-independent actions, such as promotion of cancer cell migration an IGF-independent mechanism that involves binding prohibitin-2 (Fu et al., 2007; Fu et al., 2013) and angiogenesis (Zhang et al., 2012). It has been reported to be a tumor suppressor in nasopharyngeal cancer through regulation of EGR-1 expression (Kuo et al., 2010).
As well as binding IGFs with high affinity, IGFBP-6 also binds other unrelated proteins, including importin-α, prohibitin-2 and Ku80 as described above. Other proteins that bind IGFBP-6 inhibits osteoblast differentiation, which may be mediated by binding to LIM mineralization protein-1 (LMP-1) (Strohbach et al., 2008), the vitamin D receptor (Cui et al., 2011), and the thyroid hormone-α receptor (Qiu et al., 2012).
Global deletion of IGFBP6 expression does not result in a major phenotype, presumable because of functional redundancy with other IGFBPs.
Homology IGFBP-6 shares homology with IGFBPs 1-5 in its N-terminal IGF binding domain and its C-terminal domain. It shares homology in its C-domain with other proteins containing a thyroglobulin type 1 fold.
IGFBP-6 is found in mammalian species including man, cow, rat and mouse, as well as trout and salmon. The IGFBP6 gene is duplicated in zebrafish, and each gene has a distinct expression pattern; however, overexpression of either gene inhibits embryonic growth and development (Wang et al., 2009).

Implicated in

Note
  
Entity Various cancers
Note In many studies, IGFBP-6 expression is lower in (1) malignant vs normal cells; and (2) metastatic vs primary tumors, suggesting that it has an inhibitory effect on tumor development, at least in part by inhibiting IGF actions. Examples include rhabdomyosarcoma, head and neck cancer, lung cancer and gastric cancer (Bach et al., 2013). Exogenously added or overexpressed IGFBP-6 inhibits rhabdomyosarcoma and neuroblastoma xenograft growth in mice (Grellier et al., 1998; Gallicchio et al., 2001). IGFBP6 has been implicated as a tumor suppressor in nasopharyngeal cancer by its role as a transcription factor for EGR-1 (Kuo et al., 2010).
  
  
Entity Chronic renal failure
Note Circulating IGFBP-6 levels are increased in patients with chronic renal failure (Powell et al., 1997; Van Doorn et al., 1999) and this, together with increased levels of other IGFBPs, may contribute to impaired IGF action in these patients.
  
  
Entity Proliferative vitreoretinopathy
Note IGFBP-6 levels are increased in serum and vitreous from patients with this condition, and serum levels decreased after vitrectomy (Yu et al., 2014).
  
  
Entity Non islet-cell tumor hypoglycemia
Note This rare condition is due to overexpression by tumors of a partially processed form of IGF-II that does not form normal serum complexes with IGFBPs and the acid-labile subunit and therefore has increased bioavailability. IGFBP-6 levels are increased in this condition (Van Doorn et al., 1999).
  

Bibliography

Insulin-like growth factor-binding protein-6 and cancer.
Bach LA, Fu P, Yang Z.
Clin Sci (Lond). 2013 Feb;124(4):215-29. doi: 10.1042/CS20120343. (REVIEW)
PMID 23126425
 
Human insulin-like growth factor binding protein-6 is O-glycosylated.
Bach LA, Thotakura NR, Rechler MM.
Biochem Biophys Res Commun. 1992 Jul 15;186(1):301-7.
PMID 1378724
 
IGFBP-6 five years on; not so 'forgotten'?
Bach LA.
Growth Horm IGF Res. 2005 Jun;15(3):185-92. (REVIEW)
PMID 15914054
 
Radioimmunoassay of insulin-like growth factor-binding protein-6 in human serum and other body fluids.
Baxter RC, Saunders H.
J Endocrinol. 1992 Jul;134(1):133-9.
PMID 1380056
 
The N-terminal subdomain of insulin-like growth factor (IGF) binding protein 6. Structure and interaction with IGFs.
Chandrashekaran IR, Yao S, Wang CC, Bansal PS, Alewood PF, Forbes BE, Wallace JC, Bach LA, Norton RS.
Biochemistry. 2007 Mar 20;46(11):3065-74. Epub 2007 Feb 17.
PMID 17305365
 
A novel interaction between insulin-like growth factor binding protein-6 and the vitamin D receptor inhibits the role of vitamin D3 in osteoblast differentiation.
Cui J, Ma C, Qiu J, Ma X, Wang X, Chen H, Huang B.
Mol Cell Endocrinol. 2011 May 16;338(1-2):84-92. doi: 10.1016/j.mce.2011.03.011. Epub 2011 Mar 30.
PMID 21458526
 
Promotion of cancer cell migration: an insulin-like growth factor (IGF)-independent action of IGF-binding protein-6.
Fu P, Thompson JA, Bach LA.
J Biol Chem. 2007 Aug 3;282(31):22298-306. Epub 2007 May 22.
PMID 17519236
 
Prohibitin-2 binding modulates insulin-like growth factor-binding protein-6 (IGFBP-6)-induced rhabdomyosarcoma cell migration.
Fu P, Yang Z, Bach LA.
J Biol Chem. 2013 Oct 11;288(41):29890-900. doi: 10.1074/jbc.M113.510826. Epub 2013 Sep 3.
PMID 24003225
 
Overexpression of insulin-like growth factor binding protein-6 inhibits rhabdomyosarcoma growth in vivo.
Gallicchio MA, Kneen M, Hall C, Scott AM, Bach LA.
Int J Cancer. 2001 Dec 1;94(5):645-51.
PMID 11745458
 
Expression of insulin-like growth factor-binding protein 6 complementary DNA alters neuroblastoma cell growth.
Grellier P, De Galle B, Babajko S.
Cancer Res. 1998 Apr 15;58(8):1670-6.
PMID 9563481
 
C-terminal domain of insulin-like growth factor (IGF) binding protein-6: structure and interaction with IGF-II.
Headey SJ, Keizer DW, Yao S, Brasier G, Kantharidis P, Bach LA, Norton RS.
Mol Endocrinol. 2004 Nov;18(11):2740-50. Epub 2004 Aug 12.
PMID 15308688
 
A functional nuclear localization signal in insulin-like growth factor binding protein-6 mediates its nuclear import.
Iosef C, Gkourasas T, Jia CY, Li SS, Han VK.
Endocrinology. 2008 Mar;149(3):1214-26. Epub 2007 Nov 26.
PMID 18039785
 
Insulin-like growth factor binding protein-6 (IGFBP-6) interacts with DNA-end binding protein Ku80 to regulate cell fate.
Iosef C, Vilk G, Gkourasas T, Lee KJ, Chen BP, Fu P, Bach LA, Lajoie G, Gupta MB, Li SS, Han VK.
Cell Signal. 2010 Jul;22(7):1033-43. doi: 10.1016/j.cellsig.2010.02.006. Epub 2010 Feb 24.
PMID 20188166
 
MOPED: Model Organism Protein Expression Database.
Kolker E, Higdon R, Haynes W, Welch D, Broomall W, Lancet D, Stanberry L, Kolker N.
Nucleic Acids Res. 2012 Jan;40(Database issue):D1093-9. doi: 10.1093/nar/gkr1177. Epub 2011 Dec 1.
PMID 22139914
 
IGFBP-6 plays a role as an oncosuppressor gene in NPC pathogenesis through regulating EGR-1 expression.
Kuo YS, Tang YB, Lu TY, Wu HC, Lin CT.
J Pathol. 2010 Nov;222(3):299-309. doi: 10.1002/path.2735.
PMID 20635349
 
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.
Neumann GM, Bach LA.
J Biol Chem. 1999 May 21;274(21):14587-94.
PMID 10329650
 
Insulin-like growth factor-binding protein-6 levels are elevated in serum of children with chronic renal failure: a report of the Southwest Pediatric Nephrology Study Group.
Powell DR, Liu F, Baker BK, Hintz RL, Durham SK, Brewer ED, Frane JW, Tonshoff B, Mehls O, Wingen AM, Watkins SL, Hogg RJ, Lee PD.
J Clin Endocrinol Metab. 1997 Sep;82(9):2978-84.
PMID 9284730
 
Insulin-like growth factor binding protein-6 interacts with the thyroid hormone receptor ?1 and modulates the thyroid hormone-response in osteoblastic differentiation.
Qiu J, Ma XL, Wang X, Chen H, Huang BR.
Mol Cell Biochem. 2012 Feb;361(1-2):197-208. doi: 10.1007/s11010-011-1104-y. Epub 2011 Oct 14.
PMID 21997736
 
Potential involvement of the interaction between insulin-like growth factor binding protein (IGFBP)-6 and LIM mineralization protein (LMP)-1 in regulating osteoblast differentiation.
Strohbach C, Kleinman S, Linkhart T, Amaar Y, Chen ST, Mohan S, Strong D.
J Cell Biochem. 2008 Aug 1;104(5):1890-905. doi: 10.1002/jcb.21761.
PMID 18395833
 
AceView: a comprehensive cDNA-supported gene and transcripts annotation.
Thierry-Mieg D, Thierry-Mieg J.
Genome Biol. 2006;7 Suppl 1:S12.1-14. Epub 2006 Aug 7.
PMID 16925834
 
Circulating levels of human insulin-like growth factor binding protein-6 (IGFBP-6) in health and disease as determined by radioimmunoassay.
Van Doorn J, Ringeling AM, Shmueli SS, Kuijpers MC, Hokken-Koelega AC, van Buul-Offers SC, Jansen M.
Clin Endocrinol (Oxf). 1999 May;50(5):601-9.
PMID 10468926
 
Molecular and functional characterization of two distinct IGF binding protein-6 genes in zebrafish.
Wang X, Lu L, Li Y, Li M, Chen C, Feng Q, Zhang C, Duan C.
Am J Physiol Regul Integr Comp Physiol. 2009 May;296(5):R1348-57. doi: 10.1152/ajpregu.90969.2008. Epub 2009 Mar 11.
PMID 19279291
 
BioGPS and MyGene.info: organizing online, gene-centric information.
Wu C, Macleod I, Su AI.
Nucleic Acids Res. 2013 Jan;41(Database issue):D561-5. doi: 10.1093/nar/gks1114. Epub 2012 Nov 21.
PMID 23175613
 
Kininogen 1 and insulin-like growth factor binding protein 6: candidate serum biomarkers of proliferative vitreoretinopathy.
Yu J, Peng R, Chen H, Cui C, Ba J, Wang F.
Clin Exp Optom. 2014 Jan;97(1):72-9. doi: 10.1111/cxo.12088. Epub 2013 Jul 1.
PMID 23808406
 
IGF binding protein-6 expression in vascular endothelial cells is induced by hypoxia and plays a negative role in tumor angiogenesis.
Zhang C, Lu L, Li Y, Wang X, Zhou J, Liu Y, Fu P, Gallicchio MA, Bach LA, Duan C.
Int J Cancer. 2012 May 1;130(9):2003-12. doi: 10.1002/ijc.26201. Epub 2011 Aug 5.
PMID 21618524
 

Citation

This paper should be referenced as such :
LA Bach
IGFBP6 (insulin-like growth factor binding protein 6)
Atlas Genet Cytogenet Oncol Haematol. 2015;19(1):15-17.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/IGFBP6ID40933ch12q13.html


External links

Nomenclature
HGNC (Hugo)IGFBP6   5475
Cards
AtlasIGFBP6ID40933ch12q13
Entrez_Gene (NCBI)IGFBP6  3489  insulin like growth factor binding protein 6
AliasesIBP6
GeneCards (Weizmann)IGFBP6
Ensembl hg19 (Hinxton)ENSG00000167779 [Gene_View]  chr12:53491436-53496128 [Contig_View]  IGFBP6 [Vega]
Ensembl hg38 (Hinxton)ENSG00000167779 [Gene_View]  chr12:53491436-53496128 [Contig_View]  IGFBP6 [Vega]
ICGC DataPortalENSG00000167779
TCGA cBioPortalIGFBP6
AceView (NCBI)IGFBP6
Genatlas (Paris)IGFBP6
WikiGenes3489
SOURCE (Princeton)IGFBP6
Genetics Home Reference (NIH)IGFBP6
Genomic and cartography
GoldenPath hg19 (UCSC)IGFBP6  -     chr12:53491436-53496128 +  12q13   [Description]    (hg19-Feb_2009)
GoldenPath hg38 (UCSC)IGFBP6  -     12q13   [Description]    (hg38-Dec_2013)
EnsemblIGFBP6 - 12q13 [CytoView hg19]  IGFBP6 - 12q13 [CytoView hg38]
Mapping of homologs : NCBIIGFBP6 [Mapview hg19]  IGFBP6 [Mapview hg38]
OMIM146735   
Gene and transcription
Genbank (Entrez)AK313158 BC003507 BC005007 BC010162 BC011708
RefSeq transcript (Entrez)NM_002178
RefSeq genomic (Entrez)NC_000012 NC_018923 NT_029419 NW_004929384
Consensus coding sequences : CCDS (NCBI)IGFBP6
Cluster EST : UnigeneHs.274313 [ NCBI ]
CGAP (NCI)Hs.274313
Alternative Splicing GalleryENSG00000167779
Gene ExpressionIGFBP6 [ NCBI-GEO ]   IGFBP6 [ EBI - ARRAY_EXPRESS ]   IGFBP6 [ SEEK ]   IGFBP6 [ MEM ]
Gene Expression Viewer (FireBrowse)IGFBP6 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)3489
GTEX Portal (Tissue expression)IGFBP6
Protein : pattern, domain, 3D structure
UniProt/SwissProtP24592   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtP24592  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProP24592
Splice isoforms : SwissVarP24592
PhosPhoSitePlusP24592
Domaine pattern : Prosite (Expaxy)IGFBP_N_2 (PS51323)    THYROGLOBULIN_1_1 (PS00484)    THYROGLOBULIN_1_2 (PS51162)   
Domains : Interpro (EBI)Growth_fac_rcpt_    IGFBP-6    IGFBP-like    IGFBP1-6    IGFBP_1-6_chordata    Thyroglobulin_1   
Domain families : Pfam (Sanger)IGFBP (PF00219)    Thyroglobulin_1 (PF00086)   
Domain families : Pfam (NCBI)pfam00219    pfam00086   
Domain families : Smart (EMBL)IB (SM00121)  TY (SM00211)  
Conserved Domain (NCBI)IGFBP6
DMDM Disease mutations3489
Blocks (Seattle)IGFBP6
PDB (SRS)1RMJ   
PDB (PDBSum)1RMJ   
PDB (IMB)1RMJ   
PDB (RSDB)1RMJ   
Structural Biology KnowledgeBase1RMJ   
SCOP (Structural Classification of Proteins)1RMJ   
CATH (Classification of proteins structures)1RMJ   
SuperfamilyP24592
Human Protein AtlasENSG00000167779
Peptide AtlasP24592
HPRD00902
IPIIPI00029235   IPI01022800   IPI01022291   
Protein Interaction databases
DIP (DOE-UCLA)P24592
IntAct (EBI)P24592
FunCoupENSG00000167779
BioGRIDIGFBP6
STRING (EMBL)IGFBP6
ZODIACIGFBP6
Ontologies - Pathways
QuickGOP24592
Ontology : AmiGOregulation of cell growth  receptor binding  extracellular region  extracellular space  Golgi apparatus  signal transduction  negative regulation of cell proliferation  insulin-like growth factor I binding  insulin-like growth factor II binding  regulation of insulin-like growth factor receptor signaling pathway  cellular protein metabolic process  extracellular exosome  negative regulation of canonical Wnt signaling pathway  
Ontology : EGO-EBIregulation of cell growth  receptor binding  extracellular region  extracellular space  Golgi apparatus  signal transduction  negative regulation of cell proliferation  insulin-like growth factor I binding  insulin-like growth factor II binding  regulation of insulin-like growth factor receptor signaling pathway  cellular protein metabolic process  extracellular exosome  negative regulation of canonical Wnt signaling pathway  
Pathways : BIOCARTAGhrelin: Regulation of Food Intake and Energy Homeostasis [Genes]   
REACTOMEP24592 [protein]
REACTOME Pathways381426 [pathway]   
NDEx NetworkIGFBP6
Atlas of Cancer Signalling NetworkIGFBP6
Wikipedia pathwaysIGFBP6
Orthology - Evolution
OrthoDB3489
GeneTree (enSembl)ENSG00000167779
Phylogenetic Trees/Animal Genes : TreeFamIGFBP6
HOVERGENP24592
HOGENOMP24592
Homologs : HomoloGeneIGFBP6
Homology/Alignments : Family Browser (UCSC)IGFBP6
Gene fusions - Rearrangements
Fusion : MitelmanALG10B/IGFBP6 [12q12/12q13.13]  [t(12;12)(q12;q13)]  
Fusion: TCGAALG10B 12q12 IGFBP6 12q13.13 HNSC
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerIGFBP6 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)IGFBP6
dbVarIGFBP6
ClinVarIGFBP6
1000_GenomesIGFBP6 
Exome Variant ServerIGFBP6
ExAC (Exome Aggregation Consortium)IGFBP6 (select the gene name)
Genetic variants : HAPMAP3489
Genomic Variants (DGV)IGFBP6 [DGVbeta]
DECIPHER (Syndromes)12:53491436-53496128  ENSG00000167779
CONAN: Copy Number AnalysisIGFBP6 
Mutations
ICGC Data PortalIGFBP6 
TCGA Data PortalIGFBP6 
Broad Tumor PortalIGFBP6
OASIS PortalIGFBP6 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICIGFBP6  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDIGFBP6
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch IGFBP6
DgiDB (Drug Gene Interaction Database)IGFBP6
DoCM (Curated mutations)IGFBP6 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)IGFBP6 (select a term)
intoGenIGFBP6
NCG5 (London)IGFBP6
Cancer3DIGFBP6(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM146735   
Orphanet
MedgenIGFBP6
Genetic Testing Registry IGFBP6
NextProtP24592 [Medical]
TSGene3489
GENETestsIGFBP6
Huge Navigator IGFBP6 [HugePedia]
snp3D : Map Gene to Disease3489
BioCentury BCIQIGFBP6
ClinGenIGFBP6
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD3489
Chemical/Pharm GKB GenePA29708
Clinical trialIGFBP6
Miscellaneous
canSAR (ICR)IGFBP6 (select the gene name)
Other databasePDB (2JM2)
Probes
Litterature
PubMed68 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineIGFBP6
EVEXIGFBP6
GoPubMedIGFBP6
iHOPIGFBP6
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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