GREM1_MOUSE
ID GREM1_MOUSE Reviewed; 184 AA.
AC O70326;
DT 12-APR-2005, integrated into UniProtKB/Swiss-Prot.
DT 01-AUG-1998, sequence version 1.
DT 03-AUG-2022, entry version 151.
DE RecName: Full=Gremlin-1;
DE AltName: Full=Cysteine knot superfamily 1, BMP antagonist 1;
DE AltName: Full=Down-regulated in Mos-transformed cells protein;
DE Flags: Precursor;
GN Name=Grem1; Synonyms=Cktsf1b1, Drm;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=9660951; DOI=10.1016/s1097-2765(00)80067-2;
RA Hsu D.R., Economides A.N., Wang X., Eimon P.M., Harland R.M.;
RT "The Xenopus dorsalizing factor Gremlin identifies a novel family of
RT secreted proteins that antagonize BMP activities.";
RL Mol. Cell 1:673-683(1998).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA], AND TISSUE SPECIFICITY.
RC TISSUE=Spleen;
RX PubMed=10965135; DOI=10.1159/000015625;
RA Zhang Q., Topol L.Z., Athanasiou M., Copeland N.G., Gilbert D.J.,
RA Jenkins N.A., Blair D.G.;
RT "Cloning of the murine Drm gene (Cktsf1b1) and characterization of its
RT oncogene suppressible promoter.";
RL Cytogenet. Cell Genet. 89:242-251(2000).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=FVB/N; TISSUE=Colon;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [4]
RP FUNCTION, AND TISSUE SPECIFICITY.
RX PubMed=12808456; DOI=10.1038/ng1178;
RA Khokha M.K., Hsu D., Brunet L.J., Dionne M.S., Harland R.M.;
RT "Gremlin is the BMP antagonist required for maintenance of Shh and Fgf
RT signals during limb patterning.";
RL Nat. Genet. 34:303-307(2003).
RN [5]
RP FUNCTION, TISSUE SPECIFICITY, AND INDUCTION.
RX PubMed=15133038; DOI=10.1074/jbc.m403212200;
RA Pangas S.A., Jorgez C.J., Matzuk M.M.;
RT "Growth differentiation factor 9 regulates expression of the bone
RT morphogenetic protein antagonist gremlin.";
RL J. Biol. Chem. 279:32281-32286(2004).
RN [6]
RP FUNCTION.
RX PubMed=15201225; DOI=10.1242/dev.01251;
RA Michos O., Panman L., Vintersten K., Beier K., Zeller R., Zuniga A.;
RT "Gremlin-mediated BMP antagonism induces the epithelial-mesenchymal
RT feedback signaling controlling metanephric kidney and limb organogenesis.";
RL Development 131:3401-3410(2004).
CC -!- FUNCTION: Cytokine that may play an important role during
CC carcinogenesis and metanephric kidney organogenesis, as BMP a
CC antagonist required for early limb outgrowth and patterning in
CC maintaining the FGF4-SHH feedback loop (PubMed:12808456,
CC PubMed:15201225). Down-regulates the BMP4 signaling in a dose-dependent
CC manner (PubMed:15133038). Antagonist of BMP2; inhibits BMP2-mediated
CC differentiation of osteoblasts (in vitro) (By similarity). Acts as
CC inhibitor of monocyte chemotaxis (By similarity).
CC {ECO:0000250|UniProtKB:O35793, ECO:0000250|UniProtKB:O60565,
CC ECO:0000269|PubMed:12808456, ECO:0000269|PubMed:15133038,
CC ECO:0000269|PubMed:15201225}.
CC -!- SUBUNIT: Homodimer; can also form homooligomers. Interacts with BMP2;
CC can form higher oligomers with BMP2 (By similarity). Interacts with
CC SLIT1 and SLIT2 in a glycosylation-dependent manner (By similarity).
CC {ECO:0000250|UniProtKB:O35793, ECO:0000250|UniProtKB:O60565}.
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000305}.
CC -!- TISSUE SPECIFICITY: Highly expressed in spleen and to a lesser extent
CC in lung, skeletal muscle and kidney. Expressed only in non-transformed
CC cells or primary fibroblasts in culture but not in established
CC transformed or tumor derived cell lines. Broadly expressed in limb bud
CC mesenchyme but restricted to the distal limb bud mesenchyme and
CC concentrated posteriorly. Expressed in ovary especially in granulosa
CC cells of follicles of type 4. {ECO:0000269|PubMed:10965135,
CC ECO:0000269|PubMed:12808456, ECO:0000269|PubMed:15133038}.
CC -!- INDUCTION: Up-regulated by GDF9 dose-dependent manner and BMP4 in
CC granulosa cells. Highly regulated during folliculogenesis.
CC {ECO:0000269|PubMed:15133038}.
CC -!- SIMILARITY: Belongs to the DAN family. {ECO:0000305}.
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DR EMBL; AF045801; AAC40111.1; -; mRNA.
DR EMBL; AF108189; AAD54056.1; -; mRNA.
DR EMBL; BC015293; AAH15293.1; -; mRNA.
DR CCDS; CCDS16560.1; -.
DR RefSeq; NP_035954.1; NM_011824.4.
DR AlphaFoldDB; O70326; -.
DR SMR; O70326; -.
DR BioGRID; 204780; 1.
DR STRING; 10090.ENSMUSP00000097170; -.
DR GlyGen; O70326; 1 site.
DR iPTMnet; O70326; -.
DR PhosphoSitePlus; O70326; -.
DR PaxDb; O70326; -.
DR PeptideAtlas; O70326; -.
DR PRIDE; O70326; -.
DR ProteomicsDB; 271015; -.
DR Antibodypedia; 2030; 561 antibodies from 34 providers.
DR DNASU; 23892; -.
DR Ensembl; ENSMUST00000099575; ENSMUSP00000097170; ENSMUSG00000074934.
DR GeneID; 23892; -.
DR KEGG; mmu:23892; -.
DR UCSC; uc008lpp.2; mouse.
DR CTD; 26585; -.
DR MGI; MGI:1344337; Grem1.
DR VEuPathDB; HostDB:ENSMUSG00000074934; -.
DR eggNOG; ENOG502QQ5X; Eukaryota.
DR GeneTree; ENSGT00940000154209; -.
DR HOGENOM; CLU_101024_0_0_1; -.
DR InParanoid; O70326; -.
DR OMA; MPRTRCA; -.
DR PhylomeDB; O70326; -.
DR TreeFam; TF106445; -.
DR BioGRID-ORCS; 23892; 1 hit in 75 CRISPR screens.
DR ChiTaRS; Grem1; mouse.
DR PRO; PR:O70326; -.
DR Proteomes; UP000000589; Chromosome 2.
DR RNAct; O70326; protein.
DR Bgee; ENSMUSG00000074934; Expressed in nasal concha cartilage and 120 other tissues.
DR ExpressionAtlas; O70326; baseline and differential.
DR Genevisible; O70326; MM.
DR GO; GO:0009986; C:cell surface; ISO:MGI.
DR GO; GO:0005615; C:extracellular space; IDA:BHF-UCL.
DR GO; GO:0036122; F:BMP binding; ISS:UniProtKB.
DR GO; GO:0005125; F:cytokine activity; IEA:UniProtKB-KW.
DR GO; GO:0043395; F:heparan sulfate proteoglycan binding; TAS:BHF-UCL.
DR GO; GO:0042803; F:protein homodimerization activity; ISO:MGI.
DR GO; GO:0048018; F:receptor ligand activity; IPI:BHF-UCL.
DR GO; GO:0030297; F:transmembrane receptor protein tyrosine kinase activator activity; IDA:BHF-UCL.
DR GO; GO:0043184; F:vascular endothelial growth factor receptor 2 binding; IPI:BHF-UCL.
DR GO; GO:0001525; P:angiogenesis; IDA:MGI.
DR GO; GO:0009887; P:animal organ morphogenesis; IMP:MGI.
DR GO; GO:0006915; P:apoptotic process; IEA:Ensembl.
DR GO; GO:0055007; P:cardiac muscle cell differentiation; IDA:BHF-UCL.
DR GO; GO:0060379; P:cardiac muscle cell myoblast differentiation; IDA:BHF-UCL.
DR GO; GO:0002042; P:cell migration involved in sprouting angiogenesis; IDA:BHF-UCL.
DR GO; GO:0000902; P:cell morphogenesis; ISO:MGI.
DR GO; GO:0007267; P:cell-cell signaling; IMP:MGI.
DR GO; GO:0030199; P:collagen fibril organization; ISO:MGI.
DR GO; GO:0048263; P:determination of dorsal identity; ISO:MGI.
DR GO; GO:0030326; P:embryonic limb morphogenesis; IMP:MGI.
DR GO; GO:0043542; P:endothelial cell migration; IDA:BHF-UCL.
DR GO; GO:0060173; P:limb development; ISO:MGI.
DR GO; GO:0003337; P:mesenchymal to epithelial transition involved in metanephros morphogenesis; IDA:UniProtKB.
DR GO; GO:0043066; P:negative regulation of apoptotic process; ISO:MGI.
DR GO; GO:0030514; P:negative regulation of BMP signaling pathway; IMP:MGI.
DR GO; GO:0030502; P:negative regulation of bone mineralization; ISO:MGI.
DR GO; GO:1900158; P:negative regulation of bone mineralization involved in bone maturation; ISO:MGI.
DR GO; GO:0046851; P:negative regulation of bone remodeling; ISO:MGI.
DR GO; GO:1900155; P:negative regulation of bone trabecula formation; ISO:MGI.
DR GO; GO:0090090; P:negative regulation of canonical Wnt signaling pathway; ISO:MGI.
DR GO; GO:0030308; P:negative regulation of cell growth; ISO:MGI.
DR GO; GO:0032331; P:negative regulation of chondrocyte differentiation; ISO:MGI.
DR GO; GO:0002689; P:negative regulation of leukocyte chemotaxis; ISO:MGI.
DR GO; GO:0090027; P:negative regulation of monocyte chemotaxis; ISO:MGI.
DR GO; GO:0045668; P:negative regulation of osteoblast differentiation; ISS:UniProtKB.
DR GO; GO:0033689; P:negative regulation of osteoblast proliferation; ISO:MGI.
DR GO; GO:0090291; P:negative regulation of osteoclast proliferation; ISO:MGI.
DR GO; GO:0060394; P:negative regulation of pathway-restricted SMAD protein phosphorylation; ISO:MGI.
DR GO; GO:0045892; P:negative regulation of transcription, DNA-templated; IMP:UniProtKB.
DR GO; GO:0045766; P:positive regulation of angiogenesis; IMP:BHF-UCL.
DR GO; GO:0090190; P:positive regulation of branching involved in ureteric bud morphogenesis; IDA:UniProtKB.
DR GO; GO:0008284; P:positive regulation of cell population proliferation; ISO:MGI.
DR GO; GO:0051092; P:positive regulation of NF-kappaB transcription factor activity; IDA:MGI.
DR GO; GO:1901224; P:positive regulation of NIK/NF-kappaB signaling; IDA:MGI.
DR GO; GO:1900086; P:positive regulation of peptidyl-tyrosine autophosphorylation; IDA:BHF-UCL.
DR GO; GO:0061098; P:positive regulation of protein tyrosine kinase activity; IDA:BHF-UCL.
DR GO; GO:0002092; P:positive regulation of receptor internalization; IDA:BHF-UCL.
DR GO; GO:2000273; P:positive regulation of signaling receptor activity; IDA:BHF-UCL.
DR GO; GO:0051973; P:positive regulation of telomerase activity; ISO:MGI.
DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IDA:BHF-UCL.
DR GO; GO:0045893; P:positive regulation of transcription, DNA-templated; IDA:UniProtKB.
DR GO; GO:0009954; P:proximal/distal pattern formation; IMP:MGI.
DR GO; GO:0010717; P:regulation of epithelial to mesenchymal transition; ISO:MGI.
DR GO; GO:0051893; P:regulation of focal adhesion assembly; IDA:BHF-UCL.
DR GO; GO:0038098; P:sequestering of BMP from receptor via BMP binding; IBA:GO_Central.
DR GO; GO:0007165; P:signal transduction; IDA:BHF-UCL.
DR GO; GO:0060676; P:ureteric bud formation; IDA:UniProtKB.
DR Gene3D; 2.10.90.10; -; 1.
DR InterPro; IPR006207; Cys_knot_C.
DR InterPro; IPR029034; Cystine-knot_cytokine.
DR InterPro; IPR004133; DAN.
DR InterPro; IPR017159; Gremlin-1/2.
DR Pfam; PF03045; DAN; 1.
DR PIRSF; PIRSF037254; Gremlin_precursor; 1.
DR SMART; SM00041; CT; 1.
PE 2: Evidence at transcript level;
KW Cytokine; Disulfide bond; Glycoprotein; Reference proteome; Secreted;
KW Signal.
FT SIGNAL 1..24
FT /evidence="ECO:0000250"
FT CHAIN 25..184
FT /note="Gremlin-1"
FT /id="PRO_0000006716"
FT DOMAIN 94..184
FT /note="CTCK"
FT REGION 23..77
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 40..56
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT CARBOHYD 42
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 94..144
FT /evidence="ECO:0000250|UniProtKB:O60565"
FT DISULFID 108..158
FT /evidence="ECO:0000250|UniProtKB:O60565"
FT DISULFID 118..176
FT /evidence="ECO:0000250|UniProtKB:O60565"
FT DISULFID 122..178
FT /evidence="ECO:0000250|UniProtKB:O60565"
SQ SEQUENCE 184 AA; 20710 MW; D1BD99783CDC0F2D CRC64;
MNRTAYTVGA LLLLLGTLLP TAEGKKKGSQ GAIPPPDKAQ HNDSEQTQSP PQPGSRTRGR
GQGRGTAMPG EEVLESSQEA LHVTERKYLK RDWCKTQPLK QTIHEEGCNS RTIINRFCYG
QCNSFYIPRH IRKEEGSFQS CSFCKPKKFT TMMVTLNCPE LQPPTKKKRV TRVKQCRCIS
IDLD
