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O60565 (GREM1_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 106. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (3) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Interactions·Alt products·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Gremlin-1
Alternative name(s):
Cell proliferation-inducing gene 2 protein
Cysteine knot superfamily 1, BMP antagonist 1
DAN domain family member 2
Down-regulated in Mos-transformed cells protein
Increased in high glucose protein 2
Short name=IHG-2
Gene names
Name:GREM1
Synonyms:CKTSF1B1, DAND2, DRM
ORF Names:PIG2
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length184 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Cytokine that may play an important role during carcinogenesis and metanephric kidney organogenesis, as a BMP antagonist required for early limb outgrowth and patterning in maintaining the FGF4-SHH feedback loop. Down-regulates the BMP4 signaling in a dose-dependent manner. Acts as inhibitor of monocyte chemotaxis By similarity. Ref.3

Subunit structure

Interacts with SLIT1 and SLIT2 in a glycosylation-dependent manner By similarity.

Subcellular location

Secreted Probable.

Tissue specificity

Highly expressed in small intestine, fetal brain and colon. Expression is restricted to intestinal subepithelial myofibroblasts (ISEMFs) at the crypt base. In subjects with HMPS1, by contrast, GREM1 is expressed, not only in basal ISEMFs, but also at very high levels in epithelial cells (predominantly colonocytes), with expression extending most of the way up the sides of the crypt. Weakly expressed in brain, ovary, prostate, pancreas and skeletal muscle. In brain found in the region localized around the internal capsule in the large subcortical nuclei, including caudate, putamen, substantia nigra, thalamus and subthalamus. Predominantly expressed in normal cells including neurons, astrocytes and fibroblasts. Ref.3 Ref.9

Induction

By high glucose through TGFB1-mediated pathways in mesangial cell. Down-regulated in tumor cell lines. Ref.2 Ref.3

Involvement in disease

Polyposis syndrome, mixed hereditary 1 (HMPS1) [MIM:601228]: A disease characterized by apparent autosomal dominant inheritance of multiple types of colorectal polyp, with colorectal carcinoma occurring in a high proportion of affected individuals. Patients can develop polyps of multiple and mixed morphologies, including serrated lesions, Peutz-Jeghers polyps, juvenile polyps, conventional adenomas and colorectal carcinoma in the absence of any identifiable extra-colonic features.
Note: The disease is caused by mutations affecting the gene represented in this entry. HMPS1 is caused by a duplication spanning the 3' end of the SCG5 gene and a region upstream of the GREM1 locus. This duplication is associated with increased allele-specific GREM1 expression that may cause reduced bone morphogenetic protein (BMP) pathway activity. This mechanism also underlies tumorigenesis in juvenile polyposis of the large bowel (Ref.9). Ref.9

Sequence similarities

Belongs to the DAN family.

Contains 1 CTCK (C-terminal cystine knot-like) domain.

Ontologies

Keywords
   Cellular componentSecreted
   Coding sequence diversityAlternative splicing
   DomainSignal
   Molecular functionCytokine
   PTMDisulfide bond
Glycoprotein
   Technical termComplete proteome
Direct protein sequencing
Reference proteome
Gene Ontology (GO)
   Biological_processactivation of transmembrane receptor protein tyrosine kinase activity

Inferred from sequence or structural similarity. Source: GOC

apoptotic process

Inferred from electronic annotation. Source: Ensembl

branching involved in ureteric bud morphogenesis

Inferred from electronic annotation. Source: Ensembl

cell migration involved in sprouting angiogenesis

Inferred from sequence or structural similarity Ref.1. Source: BHF-UCL

cell morphogenesis

Inferred from direct assay PubMed 16545136. Source: BHF-UCL

cell-cell signaling

Inferred from electronic annotation. Source: Ensembl

collagen fibril organization

Inferred from mutant phenotype PubMed 15539560. Source: BHF-UCL

determination of dorsal identity

Inferred from mutant phenotype Ref.1. Source: BHF-UCL

embryonic limb morphogenesis

Inferred from electronic annotation. Source: Ensembl

mesenchymal to epithelial transition involved in metanephros morphogenesis

Inferred from electronic annotation. Source: Ensembl

negative regulation of BMP signaling pathway

Inferred from mutant phenotype PubMed 16816361. Source: UniProtKB

negative regulation of bone mineralization

Inferred from mutant phenotype PubMed 15539560. Source: BHF-UCL

negative regulation of bone mineralization involved in bone maturation

Inferred from mutant phenotype PubMed 15539560. Source: BHF-UCL

negative regulation of bone remodeling

Inferred from mutant phenotype PubMed 15539560. Source: BHF-UCL

negative regulation of bone trabecula formation

Inferred from mutant phenotype PubMed 15539560. Source: BHF-UCL

negative regulation of branching involved in ureteric bud morphogenesis

Inferred from electronic annotation. Source: Ensembl

negative regulation of canonical Wnt signaling pathway

Inferred from direct assay PubMed 15539560. Source: BHF-UCL

negative regulation of cell growth

Inferred from electronic annotation. Source: Ensembl

negative regulation of monocyte chemotaxis

Inferred from sequence or structural similarity. Source: BHF-UCL

negative regulation of osteoblast proliferation

Inferred from mutant phenotype PubMed 15539560. Source: BHF-UCL

negative regulation of osteoclast proliferation

Inferred from mutant phenotype PubMed 15539560. Source: BHF-UCL

negative regulation of pathway-restricted SMAD protein phosphorylation

Inferred from direct assay PubMed 15539560. Source: BHF-UCL

negative regulation of transcription, DNA-templated

Inferred from electronic annotation. Source: Ensembl

positive regulation of NF-kappaB import into nucleus

Inferred from electronic annotation. Source: Ensembl

positive regulation of NF-kappaB transcription factor activity

Inferred from electronic annotation. Source: Ensembl

positive regulation of angiogenesis

Inferred from electronic annotation. Source: Ensembl

positive regulation of branching involved in ureteric bud morphogenesis

Inferred from electronic annotation. Source: Ensembl

positive regulation of cardiac muscle cell differentiation

Inferred from sequence or structural similarity Ref.1. Source: BHF-UCL

positive regulation of cell proliferation

Inferred from direct assay PubMed 16545136. Source: BHF-UCL

positive regulation of peptidyl-tyrosine autophosphorylation

Inferred from sequence or structural similarity Ref.1. Source: BHF-UCL

positive regulation of receptor activity

Inferred from sequence or structural similarity. Source: BHF-UCL

positive regulation of receptor internalization

Inferred from sequence or structural similarity Ref.1. Source: BHF-UCL

positive regulation of telomerase activity

Inferred from direct assay PubMed 16545136. Source: BHF-UCL

positive regulation of transcription from RNA polymerase II promoter

Inferred from sequence or structural similarity Ref.1. Source: BHF-UCL

positive regulation of transcription from RNA polymerase II promoter involved in myocardial precursor cell differentiation

Inferred from sequence or structural similarity Ref.1. Source: BHF-UCL

proximal/distal pattern formation

Inferred from electronic annotation. Source: Ensembl

regulation of epithelial to mesenchymal transition

Inferred from mutant phenotype PubMed 16816361. Source: UniProtKB

regulation of focal adhesion assembly

Inferred from electronic annotation. Source: Ensembl

signal transduction

Inferred from sequence or structural similarity. Source: BHF-UCL

ureteric bud formation

Inferred from electronic annotation. Source: Ensembl

   Cellular_componentcell surface

Inferred from electronic annotation. Source: Ensembl

extracellular space

Non-traceable author statement Ref.1. Source: BHF-UCL

   Molecular_functionBMP binding

Inferred from sequence or structural similarity Ref.1. Source: BHF-UCL

morphogen activity

Inferred from sequence or structural similarity Ref.1. Source: BHF-UCL

receptor agonist activity

Inferred from sequence or structural similarity Ref.1. Source: BHF-UCL

transmembrane receptor protein tyrosine kinase activator activity

Inferred from sequence or structural similarity. Source: BHF-UCL

vascular endothelial growth factor receptor 2 binding

Inferred from sequence or structural similarity Ref.1. Source: BHF-UCL

Complete GO annotation...

Binary interactions

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]
Isoform 1 (identifier: O60565-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.
Isoform 2 (identifier: O60565-2)

The sequence of this isoform differs from the canonical sequence as follows:
     39-79: Missing.
Note: No experimental confirmation available.

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Signal peptide1 – 2424 Ref.8
Chain25 – 184160Gremlin-1
PRO_0000006714

Regions

Domain94 – 18491CTCK

Amino acid modifications

Glycosylation421N-linked (GlcNAc...) Potential
Disulfide bond94 ↔ 144 By similarity
Disulfide bond108 ↔ 158 By similarity
Disulfide bond118 ↔ 176 By similarity
Disulfide bond122 ↔ 178 By similarity

Natural variations

Alternative sequence39 – 7941Missing in isoform 2.
VSP_013321

Sequences

Sequence LengthMass (Da)Tools
Isoform 1 [UniParc].

Last modified August 1, 1998. Version 1.
Checksum: 4B588598DE12C47E

FASTA18420,697
        10         20         30         40         50         60 
MSRTAYTVGA LLLLLGTLLP AAEGKKKGSQ GAIPPPDKAQ HNDSEQTQSP QQPGSRNRGR 

        70         80         90        100        110        120 
GQGRGTAMPG EEVLESSQEA LHVTERKYLK RDWCKTQPLK QTIHEEGCNS RTIINRFCYG 

       130        140        150        160        170        180 
QCNSFYIPRH IRKEEGSFQS CSFCKPKKFT TMMVTLNCPE LQPPTKKKRV TRVKQCRCIS 


IDLD 

« Hide

Isoform 2 [UniParc].

Checksum: 757BE38B3BE75C44
Show »

FASTA14316,292

References

« Hide 'large scale' references
[1]"The Xenopus dorsalizing factor Gremlin identifies a novel family of secreted proteins that antagonize BMP activities."
Hsu D.R., Economides A.N., Wang X., Eimon P.M., Harland R.M.
Mol. Cell 1:673-683(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
[2]"IHG-2, a mesangial cell gene induced by high glucose, is human gremlin. Regulation by extracellular glucose concentration, cyclic mechanical strain, and transforming growth factor-beta1."
McMahon R., Murphy M., Clarkson M., Taal M., Mackenzie H.S., Godson C., Martin F., Brady H.R.
J. Biol. Chem. 275:9901-9904(2000) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), INDUCTION.
[3]"DRM/GREMLIN (CKTSF1B1) maps to human chromosome 15 and is highly expressed in adult and fetal brain."
Topol L.Z., Modi W.S., Koochekpour S., Blair D.G.
Cytogenet. Cell Genet. 89:79-84(2000) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, TISSUE SPECIFICITY, INDUCTION.
Tissue: Small intestine.
[4]"Human Gremlin homologue."
Tate G., Mitsuya T.
Submitted (SEP-1999) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[5]"Identification of a human cell proliferation gene."
Kim J.W.
Submitted (FEB-2003) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
[6]"Complete sequencing and characterization of 21,243 full-length human cDNAs."
Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S. expand/collapse author list , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.
Nat. Genet. 36:40-45(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
Tissue: Chondrocyte.
[7]"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
The MGC Project Team
Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
Tissue: Liver.
[8]"Signal peptide prediction based on analysis of experimentally verified cleavage sites."
Zhang Z., Henzel W.J.
Protein Sci. 13:2819-2824(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: PROTEIN SEQUENCE OF 25-39.
[9]"Hereditary mixed polyposis syndrome is caused by a 40-kb upstream duplication that leads to increased and ectopic expression of the BMP antagonist GREM1."
Jaeger E., Leedham S., Lewis A., Segditsas S., Becker M., Cuadrado P.R., Davis H., Kaur K., Heinimann K., Howarth K., East J., Taylor J., Thomas H., Tomlinson I.
Nat. Genet. 44:699-703(2012) [PubMed] [Europe PMC] [Abstract]
Cited for: TISSUE SPECIFICITY, INVOLVEMENT IN HMPS1.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
AF045800 mRNA. Translation: AAC39725.1.
AF110137 mRNA. Translation: AAF06677.1.
AF154054 mRNA. Translation: AAG23891.1.
AB032372 Genomic DNA. Translation: BAA84462.1.
AY232290 mRNA. Translation: AAP69985.1.
AK095890 mRNA. Translation: BAC04643.1.
BC069525 mRNA. Translation: AAH69525.1.
BC093778 mRNA. Translation: AAH93778.1.
BC101611 mRNA. Translation: AAI01612.1.
RefSeqNP_001178252.1. NM_001191323.1.
NP_037504.1. NM_013372.6.
UniGeneHs.40098.

3D structure databases

ProteinModelPortalO60565.
SMRO60565. Positions 71-181.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

IntActO60565. 2 interactions.
MINTMINT-7997222.
STRING9606.ENSP00000300177.

PTM databases

PhosphoSiteO60565.

Proteomic databases

PaxDbO60565.
PRIDEO60565.

Protocols and materials databases

DNASU26585.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000300177; ENSP00000300177; ENSG00000166923. [O60565-1]
ENST00000322805; ENSP00000323101; ENSG00000166923. [O60565-2]
ENST00000560830; ENSP00000453141; ENSG00000166923. [O60565-2]
GeneID26585.
KEGGhsa:26585.
UCSCuc001zhe.2. human. [O60565-1]
uc010uby.2. human. [O60565-2]

Organism-specific databases

CTD26585.
GeneCardsGC15P033010.
HGNCHGNC:2001. GREM1.
HPAHPA007526.
MIM601228. phenotype.
603054. gene.
neXtProtNX_O60565.
Orphanet157794. Hereditary mixed polyposis syndrome.
PharmGKBPA26537.
GenAtlasSearch...

Phylogenomic databases

eggNOGNOG41424.
HOGENOMHOG000237358.
HOVERGENHBG051837.
InParanoidO60565.
OMANDSEQTE.
OrthoDBEOG7Q2N7B.
PhylomeDBO60565.
TreeFamTF106445.

Gene expression databases

ArrayExpressO60565.
BgeeO60565.
CleanExHS_GREM1.
GenevestigatorO60565.

Family and domain databases

InterProIPR006207. Cys_knot_C.
IPR004133. DAN.
IPR017159. Gremlin_precursor.
[Graphical view]
PfamPF03045. DAN. 1 hit.
[Graphical view]
PIRSFPIRSF037254. Gremlin_precursor. 1 hit.
SMARTSM00041. CT. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

ChiTaRSGREM1. human.
GenomeRNAi26585.
NextBio48952.
PROO60565.
SOURCESearch...

Entry information

Entry nameGREM1_HUMAN
AccessionPrimary (citable) accession number: O60565
Secondary accession number(s): Q52LV3, Q8N914, Q8N936
Entry history
Integrated into UniProtKB/Swiss-Prot: April 12, 2005
Last sequence update: August 1, 1998
Last modified: April 16, 2014
This is version 106 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Relevant documents

SIMILARITY comments

Index of protein domains and families

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human chromosome 15

Human chromosome 15: entries, gene names and cross-references to MIM