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O60565

- GREM1_HUMAN

UniProt

O60565 - GREM1_HUMAN

Protein

Gremlin-1

Gene

GREM1

Organism
Homo sapiens (Human)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli
  1. 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. protein binding Source: IntAct
    4. receptor agonist activity Source: BHF-UCL
    5. transmembrane receptor protein tyrosine kinase activator activity Source: BHF-UCL
    6. vascular endothelial growth factor receptor 2 binding Source: BHF-UCL

    GO - Biological processi

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

    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: Chromosome 15

    Organism-specific databases

    HGNCiHGNC:2001. GREM1.

    Subcellular locationi

    Secreted Curated

    GO - Cellular componenti

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

    Keywords - Cellular componenti

    Secreted

    Pathology & Biotechi

    Involvement in diseasei

    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.1 Publication
    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 (PubMed:22561515).1 Publication

    Organism-specific databases

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

    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

    ArrayExpressiO60565.
    BgeeiO60565.
    CleanExiHS_GREM1.
    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.
    HOGENOMiHOG000237358.
    HOVERGENiHBG051837.
    InParanoidiO60565.
    OMAiITRVKEC.
    OrthoDBiEOG7Q2N7B.
    PhylomeDBiO60565.
    TreeFamiTF106445.

    Family and domain databases

    InterProiIPR006207. Cys_knot_C.
    IPR004133. DAN.
    IPR017159. Gremlin_precursor.
    [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. Align

    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

    MSRTAYTVGA LLLLLGTLLP AAEGKKKGSQ GAIPPPDKAQ HNDSEQTQSP    50
    QQPGSRNRGR GQGRGTAMPG EEVLESSQEA LHVTERKYLK RDWCKTQPLK 100
    QTIHEEGCNS RTIINRFCYG QCNSFYIPRH IRKEEGSFQS CSFCKPKKFT 150
    TMMVTLNCPE LQPPTKKKRV TRVKQCRCIS IDLD 184
    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:
    EMBL
    GenBank
    DDBJ
    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]
    GeneIDi26585.
    KEGGihsa:26585.
    UCSCiuc001zhe.2. human. [O60565-1]
    uc010uby.2. human. [O60565-2]

    Keywords - Coding sequence diversityi

    Alternative splicing

    Cross-referencesi

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    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 .
    CCDSi CCDS10029.1. [O60565-1 ]
    CCDS53927.1. [O60565-2 ]
    RefSeqi NP_001178252.1. NM_001191323.1. [O60565-2 ]
    NP_037504.1. NM_013372.6. [O60565-1 ]
    UniGenei Hs.40098.

    3D structure databases

    ProteinModelPortali O60565.
    SMRi O60565. Positions 71-181.
    ModBasei Search...
    MobiDBi Search...

    Protein-protein interaction databases

    IntActi O60565. 2 interactions.
    MINTi MINT-7997222.
    STRINGi 9606.ENSP00000300177.

    PTM databases

    PhosphoSitei O60565.

    Proteomic databases

    MaxQBi O60565.
    PaxDbi O60565.
    PRIDEi O60565.

    Protocols and materials databases

    DNASUi 26585.
    Structural Biology Knowledgebase Search...

    Genome annotation databases

    Ensembli ENST00000560830 ; ENSP00000453141 ; ENSG00000166923 . [O60565-2 ]
    GeneIDi 26585.
    KEGGi hsa:26585.
    UCSCi uc001zhe.2. human. [O60565-1 ]
    uc010uby.2. human. [O60565-2 ]

    Organism-specific databases

    CTDi 26585.
    GeneCardsi GC15P033010.
    HGNCi HGNC:2001. GREM1.
    HPAi HPA007526.
    MIMi 601228. phenotype.
    603054. gene.
    neXtProti NX_O60565.
    Orphaneti 157794. Hereditary mixed polyposis syndrome.
    PharmGKBi PA26537.
    GenAtlasi Search...

    Phylogenomic databases

    eggNOGi NOG41424.
    HOGENOMi HOG000237358.
    HOVERGENi HBG051837.
    InParanoidi O60565.
    OMAi ITRVKEC.
    OrthoDBi EOG7Q2N7B.
    PhylomeDBi O60565.
    TreeFami TF106445.

    Miscellaneous databases

    ChiTaRSi GREM1. human.
    GenomeRNAii 26585.
    NextBioi 48952.
    PROi O60565.
    SOURCEi Search...

    Gene expression databases

    ArrayExpressi O60565.
    Bgeei O60565.
    CleanExi HS_GREM1.
    Genevestigatori O60565.

    Family and domain databases

    InterProi IPR006207. Cys_knot_C.
    IPR004133. DAN.
    IPR017159. Gremlin_precursor.
    [Graphical view ]
    Pfami PF03045. DAN. 1 hit.
    [Graphical view ]
    PIRSFi PIRSF037254. Gremlin_precursor. 1 hit.
    SMARTi SM00041. CT. 1 hit.
    [Graphical view ]
    ProtoNeti Search...

    Publicationsi

    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: October 1, 2014
    This is version 110 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