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Protein

Gremlin-1

Gene

GREM1

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-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. Acts as inhibitor of monocyte chemotaxis (By similarity).By similarity

GO - Molecular functioni

  1. BMP binding Source: BHF-UCL
  2. morphogen activity Source: BHF-UCL
  3. receptor agonist activity Source: BHF-UCL
  4. transmembrane receptor protein tyrosine kinase activator activity Source: BHF-UCL
  5. vascular endothelial growth factor receptor 2 binding Source: BHF-UCL

GO - Biological processi

  1. apoptotic process Source: Ensembl
  2. branching involved in ureteric bud morphogenesis Source: Ensembl
  3. cell-cell signaling Source: Ensembl
  4. cell migration involved in sprouting angiogenesis Source: BHF-UCL
  5. cell morphogenesis Source: BHF-UCL
  6. collagen fibril organization Source: BHF-UCL
  7. determination of dorsal identity Source: BHF-UCL
  8. embryonic limb morphogenesis Source: Ensembl
  9. limb development Source: AgBase
  10. mesenchymal to epithelial transition involved in metanephros morphogenesis Source: Ensembl
  11. negative regulation of apoptotic process Source: AgBase
  12. negative regulation of BMP signaling pathway Source: UniProtKB
  13. negative regulation of bone mineralization Source: BHF-UCL
  14. negative regulation of bone mineralization involved in bone maturation Source: BHF-UCL
  15. negative regulation of bone remodeling Source: BHF-UCL
  16. negative regulation of bone trabecula formation Source: BHF-UCL
  17. negative regulation of branching involved in ureteric bud morphogenesis Source: Ensembl
  18. negative regulation of canonical Wnt signaling pathway Source: BHF-UCL
  19. negative regulation of cell growth Source: Ensembl
  20. negative regulation of chondrocyte differentiation Source: AgBase
  21. negative regulation of monocyte chemotaxis Source: BHF-UCL
  22. negative regulation of osteoblast proliferation Source: BHF-UCL
  23. negative regulation of osteoclast proliferation Source: BHF-UCL
  24. negative regulation of pathway-restricted SMAD protein phosphorylation Source: BHF-UCL
  25. negative regulation of transcription, DNA-templated Source: Ensembl
  26. positive regulation of angiogenesis Source: Ensembl
  27. positive regulation of branching involved in ureteric bud morphogenesis Source: Ensembl
  28. positive regulation of cardiac muscle cell differentiation Source: BHF-UCL
  29. positive regulation of cell proliferation Source: BHF-UCL
  30. positive regulation of NF-kappaB import into nucleus Source: Ensembl
  31. positive regulation of NF-kappaB transcription factor activity Source: Ensembl
  32. positive regulation of peptidyl-tyrosine autophosphorylation Source: BHF-UCL
  33. positive regulation of receptor activity Source: BHF-UCL
  34. positive regulation of receptor internalization Source: BHF-UCL
  35. positive regulation of telomerase activity Source: BHF-UCL
  36. positive regulation of transcription from RNA polymerase II promoter Source: BHF-UCL
  37. positive regulation of transcription from RNA polymerase II promoter involved in myocardial precursor cell differentiation Source: BHF-UCL
  38. proximal/distal pattern formation Source: Ensembl
  39. regulation of epithelial to mesenchymal transition Source: UniProtKB
  40. regulation of focal adhesion assembly Source: Ensembl
  41. signal transduction Source: BHF-UCL
  42. ureteric bud formation Source: Ensembl
Complete GO annotation...

Keywords - Molecular functioni

Cytokine

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 2
Short name:
IHG-2
Gene namesi
Name:GREM1
Synonyms:CKTSF1B1, DAND2, DRM
ORF Names:PIG2
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
ProteomesiUP000005640 Componentsi: Chromosome 15, Unplaced

Organism-specific databases

HGNCiHGNC:2001. GREM1.

Subcellular locationi

  1. Secreted Curated

GO - Cellular componenti

  1. cell surface Source: Ensembl
  2. extracellular space Source: BHF-UCL
Complete GO annotation...

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).

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

MIMi601228. phenotype.
Orphaneti157794. Hereditary mixed polyposis syndrome.
PharmGKBiPA26537.

Polymorphism and mutation databases

BioMutaiGREM1.

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Signal peptidei1 – 24241 PublicationAdd
BLAST
Chaini25 – 184160Gremlin-1PRO_0000006714Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Glycosylationi42 – 421N-linked (GlcNAc...)Sequence Analysis
Disulfide bondi94 ↔ 144By similarity
Disulfide bondi108 ↔ 158By similarity
Disulfide bondi118 ↔ 176By similarity
Disulfide bondi122 ↔ 178By similarity

Keywords - PTMi

Disulfide bond, Glycoprotein

Proteomic databases

MaxQBiO60565.
PaxDbiO60565.
PRIDEiO60565.

PTM databases

PhosphoSiteiO60565.

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

BgeeiO60565.
CleanExiHS_GREM1.
ExpressionAtlasiO60565. baseline and differential.
GenevestigatoriO60565.

Organism-specific databases

HPAiHPA007526.

Interactioni

Subunit structurei

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

Binary interactionsi

WithEntry#Exp.IntActNotes
KDRP359684EBI-944395,EBI-1005487
YWHAHQ049175EBI-944395,EBI-306940

Protein-protein interaction databases

IntActiO60565. 2 interactions.
MINTiMINT-7997222.
STRINGi9606.ENSP00000300177.

Structurei

3D structure databases

ProteinModelPortaliO60565.
SMRiO60565. Positions 71-181.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini94 – 18491CTCKAdd
BLAST

Sequence similaritiesi

Belongs to the DAN family.Curated

Keywords - Domaini

Signal

Phylogenomic databases

eggNOGiNOG41424.
GeneTreeiENSGT00510000046909.
HOGENOMiHOG000237358.
HOVERGENiHBG051837.
InParanoidiO60565.
OMAiRVKECRC.
OrthoDBiEOG7Q2N7B.
PhylomeDBiO60565.
TreeFamiTF106445.

Family and domain databases

InterProiIPR006207. Cys_knot_C.
IPR004133. DAN.
IPR017159. Gremlin-1/2.
[Graphical view]
PfamiPF03045. DAN. 1 hit.
[Graphical view]
PIRSFiPIRSF037254. Gremlin_precursor. 1 hit.
SMARTiSM00041. CT. 1 hit.
[Graphical view]

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)LengthDescriptionGraphical viewFeature identifierActions
Alternative sequencei39 – 7941Missing in isoform 2. 1 PublicationVSP_013321Add
BLAST

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

EnsembliENST00000300177; ENSP00000300177; ENSG00000276886. [O60565-1]
ENST00000322805; ENSP00000323101; ENSG00000276886. [O60565-2]
ENST00000560830; ENSP00000453141; ENSG00000166923. [O60565-2]
ENST00000622074; ENSP00000478319; ENSG00000166923. [O60565-1]
GeneIDi26585.
KEGGihsa:26585.
UCSCiuc001zhe.2. human. [O60565-1]
uc010uby.2. human. [O60565-2]

Polymorphism and mutation databases

BioMutaiGREM1.

Keywords - Coding sequence diversityi

Alternative splicing

Cross-referencesi

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.

3D structure databases

ProteinModelPortaliO60565.
SMRiO60565. Positions 71-181.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

IntActiO60565. 2 interactions.
MINTiMINT-7997222.
STRINGi9606.ENSP00000300177.

PTM databases

PhosphoSiteiO60565.

Polymorphism and mutation databases

BioMutaiGREM1.

Proteomic databases

MaxQBiO60565.
PaxDbiO60565.
PRIDEiO60565.

Protocols and materials databases

DNASUi26585.
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000300177; ENSP00000300177; ENSG00000276886. [O60565-1]
ENST00000322805; ENSP00000323101; ENSG00000276886. [O60565-2]
ENST00000560830; ENSP00000453141; ENSG00000166923. [O60565-2]
ENST00000622074; ENSP00000478319; ENSG00000166923. [O60565-1]
GeneIDi26585.
KEGGihsa:26585.
UCSCiuc001zhe.2. human. [O60565-1]
uc010uby.2. human. [O60565-2]

Organism-specific databases

CTDi26585.
GeneCardsiGC15P033010.
HGNCiHGNC:2001. GREM1.
HPAiHPA007526.
MIMi601228. phenotype.
603054. gene.
neXtProtiNX_O60565.
Orphaneti157794. Hereditary mixed polyposis syndrome.
PharmGKBiPA26537.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiNOG41424.
GeneTreeiENSGT00510000046909.
HOGENOMiHOG000237358.
HOVERGENiHBG051837.
InParanoidiO60565.
OMAiRVKECRC.
OrthoDBiEOG7Q2N7B.
PhylomeDBiO60565.
TreeFamiTF106445.

Miscellaneous databases

ChiTaRSiGREM1. human.
GenomeRNAii26585.
NextBioi48952.
PROiO60565.
SOURCEiSearch...

Gene expression databases

BgeeiO60565.
CleanExiHS_GREM1.
ExpressionAtlasiO60565. baseline and differential.
GenevestigatoriO60565.

Family and domain databases

InterProiIPR006207. Cys_knot_C.
IPR004133. DAN.
IPR017159. Gremlin-1/2.
[Graphical view]
PfamiPF03045. DAN. 1 hit.
[Graphical view]
PIRSFiPIRSF037254. Gremlin_precursor. 1 hit.
SMARTiSM00041. CT. 1 hit.
[Graphical view]
ProtoNetiSearch...

Publicationsi

« Hide 'large scale' publications
  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.
    , 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.

Entry informationi

Entry nameiGREM1_HUMAN
AccessioniPrimary (citable) accession number: O60565
Secondary accession number(s): Q52LV3, Q8N914, Q8N936
Entry historyi
Integrated into UniProtKB/Swiss-Prot: April 12, 2005
Last sequence update: August 1, 1998
Last modified: April 29, 2015
This is version 116 of the entry and version 1 of the sequence. [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

Complete proteome, Direct protein sequencing, Reference proteome

Documents

  1. Human chromosome 15
    Human chromosome 15: entries, gene names and cross-references to MIM
  2. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  3. SIMILARITY comments
    Index of protein domains and families

External Data

Dasty 3

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into Uniref entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.