IBP6_HUMAN
ID IBP6_HUMAN Reviewed; 240 AA.
AC P24592; Q14492;
DT 01-MAR-1992, integrated into UniProtKB/Swiss-Prot.
DT 01-MAR-1992, sequence version 1.
DT 03-AUG-2022, entry version 211.
DE RecName: Full=Insulin-like growth factor-binding protein 6 {ECO:0000305};
DE Short=IBP-6;
DE Short=IGF-binding protein 6;
DE Short=IGFBP-6;
DE Flags: Precursor;
GN Name=IGFBP6 {ECO:0000312|HGNC:HGNC:5475}; Synonyms=IBP6;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Osteosarcoma;
RX PubMed=1709161; DOI=10.1016/s0021-9258(18)31549-7;
RA Kiefer M.C., Masiarz F.R., Bauer D.M., Zapf J.;
RT "Identification and molecular cloning of two new 30-kDa insulin-like growth
RT factor binding proteins isolated from adult human serum.";
RL J. Biol. Chem. 266:9043-9049(1991).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=10087296; DOI=10.1007/s003359901005;
RA Ehrenborg E., Zazzi H., Lagercrantz S., Granqvist M., Hillerbrand U.,
RA Allander S.V., Larsson C., Luthman H.;
RT "Characterization and chromosomal localization of the human insulin-like
RT growth factor-binding protein 6 gene.";
RL Mamm. Genome 10:376-380(1999).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS GLY-128 AND GLN-217.
RG NIEHS SNPs program;
RL Submitted (OCT-2003) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Pancreas;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 2-240.
RC TISSUE=Placenta;
RX PubMed=1719383; DOI=10.1210/mend-5-7-938;
RA Shimasaki S., Gao L., Shimonaka M., Ling N.;
RT "Isolation and molecular cloning of insulin-like growth factor-binding
RT protein-6.";
RL Mol. Endocrinol. 5:938-948(1991).
RN [6]
RP PROTEIN SEQUENCE OF 28-57.
RC TISSUE=Serum;
RX PubMed=1697583; DOI=10.1016/s0021-9258(18)77200-1;
RA Zapf J., Kiefer M., Merryweather J., Musiarz F., Bauer D., Born W.,
RA Fischer J.A., Froesch E.R.;
RT "Isolation from adult human serum of four insulin-like growth factor (IGF)
RT binding proteins and molecular cloning of one of them that is increased by
RT IGF I administration and in extrapancreatic tumor hypoglycemia.";
RL J. Biol. Chem. 265:14892-14898(1990).
RN [7]
RP PRELIMINARY PROTEIN SEQUENCE OF 28-42.
RC TISSUE=Cerebrospinal fluid;
RX PubMed=2551732; DOI=10.1016/0014-5793(89)81101-9;
RA Roghani M., Hossenlopp P., Lepage P., Balland A., Binoux M.;
RT "Isolation from human cerebrospinal fluid of a new insulin-like growth
RT factor-binding protein with a selective affinity for IGF-II.";
RL FEBS Lett. 255:253-258(1989).
RN [8]
RP PROTEIN SEQUENCE OF 28-42.
RC TISSUE=Fibroblast;
RX PubMed=2154495; DOI=10.1016/s0021-9258(19)39711-x;
RA Martin J.L., Willetts K.E., Baxter R.C.;
RT "Purification and properties of a novel insulin-like growth factor-II
RT binding protein from transformed human fibroblasts.";
RL J. Biol. Chem. 265:4124-4130(1990).
RN [9]
RP PROTEIN SEQUENCE OF 28-42.
RC TISSUE=Osteosarcoma;
RX PubMed=1850257; DOI=10.1016/0006-291x(91)90911-p;
RA Andress D.L., Birnbaum R.S.;
RT "A novel human insulin-like growth factor binding protein secreted by
RT osteoblast-like cells.";
RL Biochem. Biophys. Res. Commun. 176:213-218(1991).
RN [10]
RP GLYCOSYLATION AT THR-126; SER-144; THR-145; THR-146 AND SER-152.
RX PubMed=9572875; DOI=10.1021/bi972894e;
RA Neumann G.M., Marinaro J.A., Bach L.A.;
RT "Identification of O-glycosylation sites and partial characterization of
RT carbohydrate structure and disulfide linkages of human insulin-like growth
RT factor binding protein 6.";
RL Biochemistry 37:6572-6585(1998).
RN [11]
RP DISULFIDE BONDS.
RX PubMed=10329650; DOI=10.1074/jbc.274.21.14587;
RA Neumann G.M., Bach L.A.;
RT "The N-terminal disulfide linkages of human insulin-like growth factor-
RT binding protein-6 (hIGFBP-6) and hIGFBP-1 are different as determined by
RT mass spectrometry.";
RL J. Biol. Chem. 274:14587-14594(1999).
RN [12]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT THR-126, AND STRUCTURE OF
RP CARBOHYDRATES.
RC TISSUE=Cerebrospinal fluid;
RX PubMed=19838169; DOI=10.1038/nmeth.1392;
RA Nilsson J., Rueetschi U., Halim A., Hesse C., Carlsohn E., Brinkmalm G.,
RA Larson G.;
RT "Enrichment of glycopeptides for glycan structure and attachment site
RT identification.";
RL Nat. Methods 6:809-811(2009).
RN [13]
RP FUNCTION, INTERACTION WITH PHB2, AND SUBCELLULAR LOCATION.
RX PubMed=24003225; DOI=10.1074/jbc.m113.510826;
RA Fu P., Yang Z., Bach L.A.;
RT "Prohibitin-2 binding modulates insulin-like growth factor-binding protein-
RT 6 (IGFBP-6)-induced rhabdomyosarcoma cell migration.";
RL J. Biol. Chem. 288:29890-29900(2013).
CC -!- FUNCTION: IGF-binding proteins prolong the half-life of the IGFs and
CC have been shown to either inhibit or stimulate the growth promoting
CC effects of the IGFs on cell culture. They alter the interaction of IGFs
CC with their cell surface receptors. Activates the MAPK signaling pathway
CC and induces cell migration (PubMed:24003225).
CC {ECO:0000269|PubMed:24003225}.
CC -!- SUBUNIT: Interacts (via C-terminal domain) with PHB2.
CC {ECO:0000269|PubMed:24003225}.
CC -!- INTERACTION:
CC P24592; P05187: ALPP; NbExp=3; IntAct=EBI-947015, EBI-1211484;
CC P24592; X5D778: ANKRD11; NbExp=3; IntAct=EBI-947015, EBI-17183751;
CC P24592; P29972: AQP1; NbExp=3; IntAct=EBI-947015, EBI-745213;
CC P24592; Q96LT6: C1orf74; NbExp=3; IntAct=EBI-947015, EBI-12049899;
CC P24592; Q8IYX3: CCDC116; NbExp=3; IntAct=EBI-947015, EBI-744311;
CC P24592; Q7Z6N9: CCDC28A; NbExp=3; IntAct=EBI-947015, EBI-10258115;
CC P24592; O14735: CDIPT; NbExp=3; IntAct=EBI-947015, EBI-358858;
CC P24592; Q02930-3: CREB5; NbExp=3; IntAct=EBI-947015, EBI-10192698;
CC P24592; Q12805: EFEMP1; NbExp=3; IntAct=EBI-947015, EBI-536772;
CC P24592; O95967: EFEMP2; NbExp=3; IntAct=EBI-947015, EBI-743414;
CC P24592; Q9H0I2: ENKD1; NbExp=3; IntAct=EBI-947015, EBI-744099;
CC P24592; Q9UM22: EPDR1; NbExp=3; IntAct=EBI-947015, EBI-946972;
CC P24592; O95995: GAS8; NbExp=3; IntAct=EBI-947015, EBI-1052570;
CC P24592; O43681: GET3; NbExp=3; IntAct=EBI-947015, EBI-2515857;
CC P24592; P24592: IGFBP6; NbExp=3; IntAct=EBI-947015, EBI-947015;
CC P24592; P60410: KRTAP10-8; NbExp=3; IntAct=EBI-947015, EBI-10171774;
CC P24592; Q6L8G8: KRTAP5-7; NbExp=3; IntAct=EBI-947015, EBI-11987425;
CC P24592; P26371: KRTAP5-9; NbExp=3; IntAct=EBI-947015, EBI-3958099;
CC P24592; O95983-2: MBD3; NbExp=3; IntAct=EBI-947015, EBI-11978579;
CC P24592; O14770-4: MEIS2; NbExp=3; IntAct=EBI-947015, EBI-8025850;
CC P24592; A6NI15: MSGN1; NbExp=3; IntAct=EBI-947015, EBI-11991020;
CC P24592; P61601: NCALD; NbExp=3; IntAct=EBI-947015, EBI-749635;
CC P24592; Q6IQ23-2: PLEKHA7; NbExp=3; IntAct=EBI-947015, EBI-12069346;
CC P24592; Q12837: POU4F2; NbExp=3; IntAct=EBI-947015, EBI-17236143;
CC P24592; P53611: RABGGTB; NbExp=3; IntAct=EBI-947015, EBI-536715;
CC P24592; Q6VN20: RANBP10; NbExp=3; IntAct=EBI-947015, EBI-310569;
CC P24592; O00560: SDCBP; NbExp=3; IntAct=EBI-947015, EBI-727004;
CC P24592; O43765: SGTA; NbExp=3; IntAct=EBI-947015, EBI-347996;
CC P24592; P49901: SMCP; NbExp=3; IntAct=EBI-947015, EBI-750494;
CC P24592; Q9BSL1: UBAC1; NbExp=3; IntAct=EBI-947015, EBI-749370;
CC P24592; Q9UMX0: UBQLN1; NbExp=3; IntAct=EBI-947015, EBI-741480;
CC P24592; Q9UHD9: UBQLN2; NbExp=3; IntAct=EBI-947015, EBI-947187;
CC P24592; Q8TAU3: ZNF417; NbExp=5; IntAct=EBI-947015, EBI-740727;
CC P24592; Q96SQ5: ZNF587; NbExp=3; IntAct=EBI-947015, EBI-6427977;
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000305|PubMed:24003225}.
CC -!- PTM: O-linked glycans consist of hexose (probably Gal), N-
CC acetylhexosamine (probably GalNAc) and sialic acid residues. O-
CC glycosylated with core 1 or possibly core 8 glycans. O-glycosylated on
CC one site only in the region AA 143-168 in cerebrospinal fluid.
CC {ECO:0000269|PubMed:19838169, ECO:0000269|PubMed:9572875}.
CC -!- WEB RESOURCE: Name=NIEHS-SNPs;
CC URL="http://egp.gs.washington.edu/data/igfbp6/";
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DR EMBL; M62402; AAB06187.1; -; mRNA.
DR EMBL; AJ006952; CAA07346.1; -; Genomic_DNA.
DR EMBL; AY443494; AAR05445.1; -; Genomic_DNA.
DR EMBL; BC003507; AAH03507.1; -; mRNA.
DR EMBL; BC005007; AAH05007.1; -; mRNA.
DR EMBL; BC010162; AAH10162.1; -; mRNA.
DR EMBL; BC011708; AAH11708.1; -; mRNA.
DR EMBL; M69054; AAA88070.1; -; mRNA.
DR CCDS; CCDS8846.1; -.
DR PIR; A39842; A39842.
DR PIR; S05699; S05699.
DR RefSeq; NP_002169.1; NM_002178.2.
DR PDB; 1RMJ; NMR; -; A=161-240.
DR PDBsum; 1RMJ; -.
DR AlphaFoldDB; P24592; -.
DR SMR; P24592; -.
DR BioGRID; 109710; 50.
DR IntAct; P24592; 40.
DR MINT; P24592; -.
DR STRING; 9606.ENSP00000301464; -.
DR BindingDB; P24592; -.
DR ChEMBL; CHEMBL2139; -.
DR DrugBank; DB01277; Mecasermin.
DR MEROPS; I31.952; -.
DR GlyConnect; 656; 2 O-Linked glycans (1 site).
DR GlyGen; P24592; 5 sites, 6 O-linked glycans (4 sites).
DR iPTMnet; P24592; -.
DR PhosphoSitePlus; P24592; -.
DR BioMuta; IGFBP6; -.
DR DMDM; 124068; -.
DR EPD; P24592; -.
DR jPOST; P24592; -.
DR MassIVE; P24592; -.
DR MaxQB; P24592; -.
DR PaxDb; P24592; -.
DR PeptideAtlas; P24592; -.
DR PRIDE; P24592; -.
DR ProteomicsDB; 54218; -.
DR Antibodypedia; 1291; 367 antibodies from 35 providers.
DR DNASU; 3489; -.
DR Ensembl; ENST00000301464.4; ENSP00000301464.3; ENSG00000167779.9.
DR GeneID; 3489; -.
DR KEGG; hsa:3489; -.
DR MANE-Select; ENST00000301464.4; ENSP00000301464.3; NM_002178.3; NP_002169.1.
DR UCSC; uc001sbu.2; human.
DR CTD; 3489; -.
DR DisGeNET; 3489; -.
DR GeneCards; IGFBP6; -.
DR HGNC; HGNC:5475; IGFBP6.
DR HPA; ENSG00000167779; Low tissue specificity.
DR MIM; 146735; gene.
DR neXtProt; NX_P24592; -.
DR OpenTargets; ENSG00000167779; -.
DR PharmGKB; PA29708; -.
DR VEuPathDB; HostDB:ENSG00000167779; -.
DR eggNOG; ENOG502QV3Q; Eukaryota.
DR GeneTree; ENSGT00940000160528; -.
DR InParanoid; P24592; -.
DR OMA; CVDELGA; -.
DR OrthoDB; 979270at2759; -.
DR PhylomeDB; P24592; -.
DR TreeFam; TF331211; -.
DR PathwayCommons; P24592; -.
DR Reactome; R-HSA-381426; Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs).
DR SignaLink; P24592; -.
DR BioGRID-ORCS; 3489; 15 hits in 1071 CRISPR screens.
DR ChiTaRS; IGFBP6; human.
DR EvolutionaryTrace; P24592; -.
DR GeneWiki; IGFBP6; -.
DR GenomeRNAi; 3489; -.
DR Pharos; P24592; Tchem.
DR PRO; PR:P24592; -.
DR Proteomes; UP000005640; Chromosome 12.
DR RNAct; P24592; protein.
DR Bgee; ENSG00000167779; Expressed in calcaneal tendon and 192 other tissues.
DR ExpressionAtlas; P24592; baseline and differential.
DR Genevisible; P24592; HS.
DR GO; GO:0005576; C:extracellular region; TAS:Reactome.
DR GO; GO:0005615; C:extracellular space; IBA:GO_Central.
DR GO; GO:0005794; C:Golgi apparatus; IEA:Ensembl.
DR GO; GO:0042568; C:insulin-like growth factor binary complex; IMP:CAFA.
DR GO; GO:0001968; F:fibronectin binding; IBA:GO_Central.
DR GO; GO:0042802; F:identical protein binding; IPI:IntAct.
DR GO; GO:0031994; F:insulin-like growth factor I binding; IBA:GO_Central.
DR GO; GO:0031995; F:insulin-like growth factor II binding; IMP:CAFA.
DR GO; GO:0005102; F:signaling receptor binding; TAS:ParkinsonsUK-UCL.
DR GO; GO:0016477; P:cell migration; IDA:UniProtKB.
DR GO; GO:0090090; P:negative regulation of canonical Wnt signaling pathway; TAS:ParkinsonsUK-UCL.
DR GO; GO:0008285; P:negative regulation of cell population proliferation; TAS:ProtInc.
DR GO; GO:0043410; P:positive regulation of MAPK cascade; IDA:UniProtKB.
DR GO; GO:0032874; P:positive regulation of stress-activated MAPK cascade; IDA:UniProtKB.
DR GO; GO:0043567; P:regulation of insulin-like growth factor receptor signaling pathway; IBA:GO_Central.
DR GO; GO:0007165; P:signal transduction; NAS:ProtInc.
DR CDD; cd00191; TY; 1.
DR Gene3D; 4.10.800.10; -; 1.
DR InterPro; IPR009030; Growth_fac_rcpt_cys_sf.
DR InterPro; IPR022326; IGFBP-6.
DR InterPro; IPR000867; IGFBP-like.
DR InterPro; IPR022321; IGFBP_1-6_chordata.
DR InterPro; IPR000716; Thyroglobulin_1.
DR InterPro; IPR036857; Thyroglobulin_1_sf.
DR PANTHER; PTHR11551:SF14; PTHR11551:SF14; 1.
DR Pfam; PF00086; Thyroglobulin_1; 1.
DR PRINTS; PR01976; IGFBPFAMILY.
DR PRINTS; PR01982; IGFBPFAMILY6.
DR SMART; SM00121; IB; 1.
DR SMART; SM00211; TY; 1.
DR SUPFAM; SSF57184; SSF57184; 1.
DR SUPFAM; SSF57610; SSF57610; 1.
DR PROSITE; PS51323; IGFBP_N_2; 1.
DR PROSITE; PS00484; THYROGLOBULIN_1_1; 1.
DR PROSITE; PS51162; THYROGLOBULIN_1_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Direct protein sequencing; Disulfide bond; Glycoprotein;
KW Growth factor binding; Reference proteome; Secreted; Signal.
FT SIGNAL 1..27
FT /evidence="ECO:0000305|PubMed:1697583,
FT ECO:0000305|PubMed:1850257, ECO:0000305|PubMed:2154495"
FT CHAIN 28..240
FT /note="Insulin-like growth factor-binding protein 6"
FT /id="PRO_0000014389"
FT DOMAIN 28..107
FT /note="IGFBP N-terminal"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00653"
FT DOMAIN 160..234
FT /note="Thyroglobulin type-1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00500"
FT REGION 109..160
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 217..240
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 126..156
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 225..240
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT CARBOHYD 126
FT /note="O-linked (HexNAc...) threonine"
FT /evidence="ECO:0000269|PubMed:19838169,
FT ECO:0000269|PubMed:9572875"
FT CARBOHYD 144
FT /note="O-linked (HexNAc...) serine"
FT /evidence="ECO:0000250"
FT CARBOHYD 145
FT /note="O-linked (HexNAc...) threonine"
FT /evidence="ECO:0000250"
FT CARBOHYD 146
FT /note="O-linked (HexNAc...) threonine"
FT /evidence="ECO:0000250"
FT CARBOHYD 152
FT /note="O-linked (HexNAc...) serine"
FT /evidence="ECO:0000250"
FT DISULFID 29..32
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00500,
FT ECO:0000269|PubMed:10329650"
FT DISULFID 40..44
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00500,
FT ECO:0000269|PubMed:10329650"
FT DISULFID 57..63
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00500,
FT ECO:0000269|PubMed:10329650"
FT DISULFID 71..84
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00500,
FT ECO:0000269|PubMed:10329650"
FT DISULFID 78..104
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00500,
FT ECO:0000269|PubMed:10329650"
FT DISULFID 163..190
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00500,
FT ECO:0000269|PubMed:10329650"
FT DISULFID 201..212
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00500,
FT ECO:0000269|PubMed:10329650"
FT DISULFID 214..234
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00500,
FT ECO:0000269|PubMed:10329650"
FT VARIANT 128
FT /note="R -> G (in dbSNP:rs9658616)"
FT /evidence="ECO:0000269|Ref.3"
FT /id="VAR_018932"
FT VARIANT 134
FT /note="R -> L (in dbSNP:rs34995393)"
FT /id="VAR_049565"
FT VARIANT 217
FT /note="R -> Q (in dbSNP:rs6413498)"
FT /evidence="ECO:0000269|Ref.3"
FT /id="VAR_018933"
FT VARIANT 236
FT /note="T -> P (in dbSNP:rs1053134)"
FT /id="VAR_011907"
FT CONFLICT 2
FT /note="T -> C (in Ref. 5; AAA88070)"
FT /evidence="ECO:0000305"
FT CONFLICT 28..29
FT /note="RC -> AA (in Ref. 6; AA sequence)"
FT /evidence="ECO:0000305"
FT CONFLICT 28..29
FT /note="RC -> LA (in Ref. 8; AA sequence)"
FT /evidence="ECO:0000305"
FT CONFLICT 32
FT /note="C -> H (in Ref. 6; AA sequence)"
FT /evidence="ECO:0000305"
FT CONFLICT 55..57
FT /note="EGC -> QGG (in Ref. 6; AA sequence)"
FT /evidence="ECO:0000305"
FT HELIX 162..177
FT /evidence="ECO:0007829|PDB:1RMJ"
FT TURN 179..181
FT /evidence="ECO:0007829|PDB:1RMJ"
FT STRAND 182..188
FT /evidence="ECO:0007829|PDB:1RMJ"
FT STRAND 198..208
FT /evidence="ECO:0007829|PDB:1RMJ"
FT STRAND 212..215
FT /evidence="ECO:0007829|PDB:1RMJ"
FT TURN 226..228
FT /evidence="ECO:0007829|PDB:1RMJ"
FT TURN 231..233
FT /evidence="ECO:0007829|PDB:1RMJ"
FT STRAND 234..236
FT /evidence="ECO:0007829|PDB:1RMJ"
SQ SEQUENCE 240 AA; 25322 MW; 285308231C025009 CRC64;
MTPHRLLPPL LLLLALLLAA SPGGALARCP GCGQGVQAGC PGGCVEEEDG GSPAEGCAEA
EGCLRREGQE CGVYTPNCAP GLQCHPPKDD EAPLRALLLG RGRCLPARAP AVAEENPKES
KPQAGTARPQ DVNRRDQQRN PGTSTTPSQP NSAGVQDTEM GPCRRHLDSV LQQLQTEVYR
GAQTLYVPNC DHRGFYRKRQ CRSSQGQRRG PCWCVDRMGK SLPGSPDGNG SSSCPTGSSG
