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Protein

Gremlin-1

Gene

GREM1

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

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 (By similarity). Antagonist of BMP2; inhibits BMP2-mediated differentiation of osteoblasts (in vitro) (PubMed:27036124). Acts as inhibitor of monocyte chemotaxis. Can inhibit the growth or viability of normal cells but not transformed cells when is overexpressed (By similarity).By similarity1 Publication

GO - Molecular functioni

  • BMP binding Source: UniProtKB
  • cytokine activity Source: UniProtKB-KW
  • morphogen activity Source: BHF-UCL
  • protein homodimerization activity Source: UniProtKB
  • receptor ligand activity Source: BHF-UCL
  • transmembrane receptor protein tyrosine kinase activator activity Source: BHF-UCL
  • vascular endothelial growth factor receptor 2 binding Source: BHF-UCL

GO - Biological processi

  • apoptotic process Source: Ensembl
  • branching involved in ureteric bud morphogenesis Source: Ensembl
  • cell-cell signaling Source: Ensembl
  • cell migration involved in sprouting angiogenesis Source: BHF-UCL
  • cell morphogenesis Source: BHF-UCL
  • collagen fibril organization Source: BHF-UCL
  • determination of dorsal identity Source: BHF-UCL
  • embryonic limb morphogenesis Source: Ensembl
  • limb development Source: AgBase
  • mesenchymal to epithelial transition involved in metanephros morphogenesis Source: Ensembl
  • negative regulation of apoptotic process Source: AgBase
  • negative regulation of BMP signaling pathway Source: BHF-UCL
  • negative regulation of bone mineralization Source: BHF-UCL
  • negative regulation of bone mineralization involved in bone maturation Source: BHF-UCL
  • negative regulation of bone remodeling Source: BHF-UCL
  • negative regulation of bone trabecula formation Source: BHF-UCL
  • negative regulation of branching involved in ureteric bud morphogenesis Source: Ensembl
  • negative regulation of canonical Wnt signaling pathway Source: BHF-UCL
  • negative regulation of cell growth Source: Ensembl
  • negative regulation of chondrocyte differentiation Source: AgBase
  • negative regulation of monocyte chemotaxis Source: BHF-UCL
  • negative regulation of osteoblast differentiation Source: UniProtKB
  • negative regulation of osteoblast proliferation Source: BHF-UCL
  • negative regulation of osteoclast proliferation Source: BHF-UCL
  • negative regulation of pathway-restricted SMAD protein phosphorylation Source: BHF-UCL
  • negative regulation of transcription, DNA-templated Source: Ensembl
  • positive regulation of angiogenesis Source: Ensembl
  • positive regulation of branching involved in ureteric bud morphogenesis Source: Ensembl
  • positive regulation of cardiac muscle cell differentiation Source: BHF-UCL
  • positive regulation of cell proliferation Source: BHF-UCL
  • positive regulation of NF-kappaB transcription factor activity Source: Ensembl
  • positive regulation of NIK/NF-kappaB signaling Source: Ensembl
  • positive regulation of peptidyl-tyrosine autophosphorylation Source: BHF-UCL
  • positive regulation of receptor internalization Source: BHF-UCL
  • positive regulation of signaling receptor activity Source: BHF-UCL
  • positive regulation of telomerase activity Source: BHF-UCL
  • positive regulation of transcription by RNA polymerase II Source: BHF-UCL
  • positive regulation of transcription from RNA polymerase II promoter involved in myocardial precursor cell differentiation Source: BHF-UCL
  • proximal/distal pattern formation Source: Ensembl
  • regulation of epithelial to mesenchymal transition Source: UniProtKB
  • regulation of focal adhesion assembly Source: Ensembl
  • signal transduction Source: BHF-UCL
  • ureteric bud formation Source: Ensembl

Keywordsi

Molecular functionCytokine

Names & Taxonomyi

Protein namesi
Recommended 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 21 Publication
Short name:
IHG-21 Publication
Gene namesi
Name:GREM1
Synonyms:CKTSF1B1, DAND2, DRM
ORF Names:PIG2
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 15

Organism-specific databases

EuPathDBiHostDB:ENSG00000166923.10
HGNCiHGNC:2001 GREM1
MIMi603054 gene
neXtProtiNX_O60565

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Secreted

Pathology & Biotechi

Involvement in diseasei

Polyposis syndrome, mixed hereditary 1 (HMPS1)1 Publication
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 (PubMed:22561515).1 Publication
Disease descriptionA 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.
See also OMIM:601228

Organism-specific databases

DisGeNETi26585
MalaCardsiGREM1
MIMi601228 phenotype
OpenTargetsiENSG00000166923
Orphaneti157794 Hereditary mixed polyposis syndrome
PharmGKBiPA26537

Polymorphism and mutation databases

BioMutaiGREM1

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Signal peptidei1 – 241 PublicationAdd BLAST24
ChainiPRO_000000671425 – 184Gremlin-1Add BLAST160

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Glycosylationi42N-linked (GlcNAc...) asparagineSequence analysis1
Disulfide bondi94 ↔ 144Combined sources1 Publication
Disulfide bondi108 ↔ 158Combined sources1 Publication
Disulfide bondi118 ↔ 176Combined sources1 Publication
Disulfide bondi122 ↔ 178Combined sources1 Publication

Keywords - PTMi

Disulfide bond, Glycoprotein

Proteomic databases

MaxQBiO60565
PaxDbiO60565
PeptideAtlasiO60565
PRIDEiO60565
ProteomicsDBi49469
49470 [O60565-2]

PTM databases

iPTMnetiO60565
PhosphoSitePlusiO60565

Expressioni

Tissue specificityi

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.2 Publications

Inductioni

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

Gene expression databases

BgeeiENSG00000166923
CleanExiHS_GREM1
ExpressionAtlasiO60565 baseline and differential
GenevisibleiO60565 HS

Organism-specific databases

HPAiHPA007526

Interactioni

Subunit structurei

Homodimer; can also form homooligomers (PubMed:27036124). Interacts with BMP2; can form higher oligomers with BMP2 (PubMed:27036124). Interacts with SLIT1 and SLIT2 in a glycosylation-dependent manner (By similarity).By similarity1 Publication

Binary interactionsi

Show more details

GO - Molecular functioni

  • BMP binding Source: UniProtKB
  • cytokine activity Source: UniProtKB-KW
  • morphogen activity Source: BHF-UCL
  • protein homodimerization activity Source: UniProtKB
  • receptor ligand activity Source: BHF-UCL
  • vascular endothelial growth factor receptor 2 binding Source: BHF-UCL

Protein-protein interaction databases

IntActiO60565, 8 interactors
MINTiO60565
STRINGi9606.ENSP00000300177

Structurei

Secondary structure

1184
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Beta strandi74 – 76Combined sources3
Helixi77 – 86Combined sources10
Turni87 – 89Combined sources3
Beta strandi93 – 103Combined sources11
Beta strandi111 – 131Combined sources21
Beta strandi134 – 157Combined sources24
Beta strandi161 – 180Combined sources20
Beta strandi182 – 184Combined sources3

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
5AEJX-ray1.90A/B/C/D72-184[»]
ProteinModelPortaliO60565
SMRiO60565
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini94 – 184CTCKAdd BLAST91

Sequence similaritiesi

Belongs to the DAN family.Curated

Keywords - Domaini

Signal

Phylogenomic databases

eggNOGiENOG410IG3Z Eukaryota
ENOG4111HEF LUCA
GeneTreeiENSGT00510000046909
HOGENOMiHOG000237358
HOVERGENiHBG051837
InParanoidiO60565
OMAiRVKECRC
OrthoDBiEOG091G0GL9
PhylomeDBiO60565
TreeFamiTF106445

Family and domain databases

Gene3Di2.10.90.10, 1 hit
InterProiView protein in InterPro
IPR006207 Cys_knot_C
IPR029034 Cystine-knot_cytokine
IPR004133 DAN
IPR017159 Gremlin-1/2
PfamiView protein in Pfam
PF03045 DAN, 1 hit
PIRSFiPIRSF037254 Gremlin_precursor, 1 hit
SMARTiView protein in SMART
SM00041 CT, 1 hit

Sequences (2)i

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: O60565-1) [UniParc]FASTAAdd to basket

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.

« Hide

        10         20         30         40         50
MSRTAYTVGA LLLLLGTLLP AAEGKKKGSQ GAIPPPDKAQ HNDSEQTQSP
60 70 80 90 100
QQPGSRNRGR GQGRGTAMPG EEVLESSQEA LHVTERKYLK RDWCKTQPLK
110 120 130 140 150
QTIHEEGCNS RTIINRFCYG QCNSFYIPRH IRKEEGSFQS CSFCKPKKFT
160 170 180
TMMVTLNCPE LQPPTKKKRV TRVKQCRCIS IDLD
Length:184
Mass (Da):20,697
Last modified:August 1, 1998 - v1
Checksum:i4B588598DE12C47E
GO
Isoform 2 (identifier: O60565-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     39-79: Missing.

Note: No experimental confirmation available.
Show »
Length:143
Mass (Da):16,292
Checksum:i757BE38B3BE75C44
GO

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_01332139 – 79Missing in isoform 2. 1 PublicationAdd BLAST41

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
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
CCDSiCCDS10029.1 [O60565-1]
CCDS53927.1 [O60565-2]
RefSeqiNP_001178252.1, NM_001191323.1 [O60565-2]
NP_037504.1, NM_013372.6 [O60565-1]
UniGeneiHs.40098

Genome annotation databases

EnsembliENST00000560830; ENSP00000453141; ENSG00000166923 [O60565-2]
ENST00000622074; ENSP00000478319; ENSG00000166923 [O60565-1]
ENST00000632478; ENSP00000488158; ENSG00000282046 [O60565-2]
ENST00000632802; ENSP00000488588; ENSG00000282046 [O60565-1]
GeneIDi26585
KEGGihsa:26585
UCSCiuc001zhe.3 human [O60565-1]

Keywords - Coding sequence diversityi

Alternative splicing

Similar proteinsi

Entry informationi

Entry nameiGREM1_HUMAN
AccessioniPrimary (citable) accession number: O60565
Secondary accession number(s): Q52LV3, Q8N914, Q8N936
Entry historyiIntegrated into UniProtKB/Swiss-Prot: April 12, 2005
Last sequence update: August 1, 1998
Last modified: June 20, 2018
This is version 144 of the entry and version 1 of the sequence. See complete history.
Entry statusiReviewed (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.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Direct protein sequencing, Reference proteome

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