Reviewed, UniProtKB/Swiss-Prot O60565 (GREM1_HUMAN)

Names and origin

Protein names

Recommended name:
    Gremlin-1
Alternative name(s):
    Cysteine knot superfamily 1, BMP antagonist 1
    Increased in high glucose protein 2
      Short name=IHG-2
    Down-regulated in Mos-transformed cells protein
    DAN domain family member 2
    Cell proliferation-inducing gene 2 protein

Gene names

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

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › 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.
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. 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
Induction	By high glucose through TGF-beta 1-mediated pathways in Mesangial cell. Down-regulated in tumor cell lines. Ref.3 Ref.2
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	Direct protein sequencing
Gene Ontology (GO)
Biological process	nervous system development Ref.1 Traceable author statement. Source: ProtInc
Cellular component	extracellular space Ref.1 Traceable author statement. Source: ProtInc
Molecular function	cytokine activity Inferred from electronic annotation. Source: UniProtKB-KW
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
YWHAH	Q04917	2	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. 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: 9660951] [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: 10744662] [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: 10894942] [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: 14702039] [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: 15489334] [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: 15340161] [Abstract] Cited for: PROTEIN SEQUENCE OF 25-39.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBLGenBankDDBJ	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_037504.1.
UniGene	Hs.40098
3D structure databases
ModBase	Search...
Protein-protein interaction databases
IntAct	O60565. 1 interaction.
PTM databases
PhosphoSite	O60565.
Proteomic databases
PRIDE	O60565.
Genome annotation databases
Ensembl	ENSG00000166923. Homo sapiens. [Contig view]
GeneID	26585.
KEGG	hsa:26585.
Organism-specific databases
GeneCards	GC15P030797.
H-InvDB	HIX0001735. HIX0012077.
HGNC	HGNC:2001. GREM1.
HPA	HPA007526.
MIM	603054. gene.
PharmGKB	PA26537.
GenAtlas	Search...
Phylogenomic databases
HOGENOM	O60565.
HOVERGEN	O60565.
OMA	O60565. NDSEQTE.
Enzyme and pathway databases
Pathway_Interaction_DB	bmppathway. BMP receptor signaling.
Gene expression databases
ArrayExpress	O60565.
Bgee	O60565.
CleanEx	HS_GREM1.
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 Resources
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:	June 16, 2009
This is version 60 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)