O60565 (GREM1_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

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 names

Name:	GREM1
Synonyms:	CKTSF1B1, DAND2, DRM
ORF Names:	PIG2

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	184 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence 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 component	Secreted
Coding sequence diversity	Alternative splicing
Domain	Signal
Molecular function	Cytokine
PTM	Disulfide bond Glycoprotein
Technical term	Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological_process	apoptotic process Inferred from electronic annotation. Source: Compara branching involved in ureteric bud morphogenesis Inferred from electronic annotation. Source: Compara 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: Compara 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: Compara mesenchymal to epithelial transition involved in metanephros morphogenesis Inferred from electronic annotation. Source: Compara negative regulation of BMP signaling pathway Inferred from mutant phenotype PubMed 16816361. Source: UniProtKB 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: Compara negative regulation of canonical Wnt receptor signaling pathway Inferred from direct assay PubMed 15539560. Source: BHF-UCL negative regulation of cell growth Inferred from electronic annotation. Source: Compara 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-dependent Inferred from electronic annotation. Source: Compara positive regulation of NF-kappaB import into nucleus Inferred from electronic annotation. Source: Compara positive regulation of NF-kappaB transcription factor activity Inferred from electronic annotation. Source: Compara positive regulation of angiogenesis Inferred from electronic annotation. Source: Compara positive regulation of branching involved in ureteric bud morphogenesis Inferred from electronic annotation. Source: Compara 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 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 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: Compara regulation of epithelial to mesenchymal transition Inferred from mutant phenotype PubMed 16816361. Source: UniProtKB regulation of focal adhesion assembly Inferred from electronic annotation. Source: Compara ureteric bud formation Inferred from electronic annotation. Source: Compara
Cellular_component	cell surface Inferred from electronic annotation. Source: Compara extracellular space Non-traceable author statement Ref.1. Source: BHF-UCL
Molecular_function	BMP 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 protein tyrosine kinase activator activity Inferred from electronic annotation. Source: Compara receptor agonist activity Inferred from sequence or structural similarity Ref.1. 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

With	Entry	#Exp.	IntAct	Notes
YWHAH	Q04917	5	EBI-944395,EBI-306940

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 key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Signal peptide	1 – 24	24	Ref.8
	Chain	25 – 184	160	Gremlin-1		PRO_0000006714
Regions
	Domain	94 – 184	91	CTCK
Amino acid modifications
	Glycosylation	42	1	N-linked (GlcNAc...) Potential
	Disulfide bond	94 ↔ 144		By similarity
	Disulfide bond	108 ↔ 158		By similarity
	Disulfide bond	118 ↔ 176		By similarity
	Disulfide bond	122 ↔ 178		By similarity
Natural variations
	Alternative sequence	39 – 79	41	Missing in isoform 2.		VSP_013321

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified August 1, 1998. Version 1. Checksum: 4B588598DE12C47E	FASTA	184	20,697
	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
	Isoform 2 [UniParc]. Checksum: 757BE38B3BE75C44	FASTA	143	16,292
	10 20 30 40 50 60 MSRTAYTVGA LLLLLGTLLP AAEGKKKGSQ GAIPPPDKAL HVTERKYLKR DWCKTQPLKQ 70 80 90 100 110 120 TIHEEGCNSR TIINRFCYGQ CNSFYIPRHI RKEEGSFQSC SFCKPKKFTT MMVTLNCPEL 130 140 QPPTKKKRVT RVKQCRCISI DLD

References

	« Hide 'large scale' referencesShow '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. , 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.
IPI	IPI00298476. IPI00747935.
RefSeq	NP_001178252.1. NM_001191323.1. NP_037504.1. NM_013372.6.
UniGene	Hs.40098.
3D structure databases
ProteinModelPortal	O60565.
ModBase	Search...
Protein-protein interaction databases
IntAct	O60565. 1 interaction.
STRING	9606.ENSP00000300177.
PTM databases
PhosphoSite	O60565.
Proteomic databases
PaxDb	O60565.
PRIDE	O60565.
Protocols and materials databases
DNASU	26585.
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENST00000300177; ENSP00000300177; ENSG00000166923. ENST00000322805; ENSP00000323101; ENSG00000166923. ENST00000560830; ENSP00000453141; ENSG00000166923.
GeneID	26585.
KEGG	hsa:26585.
UCSC	uc001zhe.2. human. uc010uby.2. human.
Organism-specific databases
CTD	26585.
GeneCards	GC15P033010.
HGNC	HGNC:2001. GREM1.
HPA	HPA007526.
MIM	601228. phenotype. 603054. gene.
neXtProt	NX_O60565.
Orphanet	157794. Hereditary mixed polyposis syndrome.
PharmGKB	PA26537.
GenAtlas	Search...
Phylogenomic databases
eggNOG	NOG41424.
HOGENOM	HOG000237358.
HOVERGEN	HBG051837.
InParanoid	O60565.
OMA	NDSEQTE.
OrthoDB	EOG4K9BDB.
PhylomeDB	O60565.
Enzyme and pathway databases
Pathway_Interaction_DB	bmppathway. BMP receptor signaling.
Gene expression databases
ArrayExpress	O60565.
Bgee	O60565.
CleanEx	HS_GREM1.
Genevestigator	O60565.
GermOnline	ENSG00000166923. Homo sapiens.
Family and domain databases
InterPro	IPR006207. Cys_knot_C. IPR004133. DAN. IPR017159. Gremlin_precursor. [Graphical view]
Pfam	PF03045. DAN. 1 hit. [Graphical view]
PIRSF	PIRSF037254. Gremlin_precursor. 1 hit.
SMART	SM00041. CT. 1 hit. [Graphical view]
PROSITE	PS01225. CTCK_2. False negative. [Graphical view]
ProtoNet	Search...
Other
ChiTaRS	GREM1. human.
GenomeRNAi	26585.
NextBio	48952.
SOURCE	Search...

Entry information

Entry name

GREM1_HUMAN

Accession

Primary (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:	May 1, 2013
This is version 97 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any 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.