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Symbol GREM1 contributors: mct/npt/pgu - updated : 27-08-2015
HGNC name gremlin 1, cysteine knot superfamily, homolog (Xenopus laevis)
HGNC id 2001
Location 15q13.3      Physical location : 33.010.204 - 33.026.871
Synonym name
  • proliferation-inducing gene 2
  • cysteine knot superfamily 1, BMP antagonist 1
  • bone morphogenetic protein antagonist 1
  • cell proliferation-inducing gene 2 protein
  • DAN domain family member 2
  • down-regulated in Mos-transformed cells protein
  • increased in high glucose protein 2
  • Synonym symbol(s) GREMLIN, IHG2, CKTSF1B1, DAND2, DRM, IHG-2, MGC126660, PIG2
    TYPE functioning gene
    STRUCTURE 16.66 kb     2 Exon(s)
    MAPPING cloned   linked N status provisional
    Map cen - D15S122 - D15S165 - SCG5 - GREM1 - D15S144 - RYR3 - qter
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    2 - 4175 - 184 - 2008 18545679
    Type widely
       expressed in (based on citations)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Digestivemouth   highly
     stomach   highly
    Reproductivefemale systemovary   
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Connectivecartilage  highly
    SystemCellPubmedSpeciesStageRna symbol
    not specificchondrocyte
    Visualrod photoreceptor
    cell lineage
    cell lines
    at STAGE
    physiological period embryo, fetal
    Text brain, neural crest, trabecular meshwork
  • C terminal cystein Knot-like domain
  • conjugated GlycoP
    interspecies homolog to Xenopus dorsalizing factor Gremlin
    homolog to Drosophila drumstick
  • cysteine knot superfamily
  • DAN family of secreted bone morphogenetic protein (BMP) antagonists
  • CATEGORY tumor suppressor
  • secreted
  • localize to hypertrophic epiphyseal chondrocytes
  • basic FUNCTION
  • involved in carcinogenesis
  • required for early limb outgrowth and patterning and moderating BMP inhibition of FGF
  • inducing epithelial-to-mesenchymal transition and having a potential role in proliferative vitreoretinopathy
  • having pro-angiogenic activity and directly binds to endothelial cells
  • activate the extracellular regulated kinase (ERK) pathway in endothelial and tumor cells, and as a consequence to have direct cellular effects
  • inhibits BMP2 signaling and activity, and does not have independent actions on ERK signaling in osteoblasts
  • its activity in osteoblasts can be attributed only to its BMP antagonizing effects
  • role in the activation of extracellular regulated kinases
  • physiological antagonist of BMPs in the skeleton, and its deletion or down-regulation sensitizes skeletal cells to the actions of BMP and Wnt, and enhances bone formation
  • has the potential to affect cells away from the mesenchyme where it is produced
  • negatively regulates the BMP pathway
  • prominent role for gremlin in central epiphyseal development compared to its role in physeal development
  • enhances the determined path to cardiomyogenesis in a stage-specific manner, and inhibition of the BMP signaling pathway is involved in initial determination of GREM1-promoted cardiomyogenesis
  • bone morphogenetic protein antagonist, may be important in mediating some of the pathological effects of TGF-beta
  • most prominent upregulated protein in the hypertrophic cell accumulation of the epiphyseal cartilage
  • regulates developing limb outgrowth, confines chondrogenesis to central core mesenchyme, and restricts apoptosis
  • necessary to negatively regulate BMP4 activity to induce ureteric bud branching
  • NOG and GREM1 cooperate potentialy to maintain a BMP signaling-free zone that is a crucial prerequisite for Hh-mediated sclerotome induction
  • NOG and GREM1 having potential role in normal tissue homeostasis as well as in malignancies
  • TGFB2, GREM1 and connective tissue growth factor (CTGF) are known to play important roles in the induction of epithelial mesenchymal transition (EMT) and extracellular matrix (ECM) synthesis
  • TGFB2, CTGF and GREM1 are all involved in EMT and ECM synthesis via activation of Smad signaling pathway in human lens epithelial cells (HLECs)
  • could participate in renal fibrosis by inducing EMT in tubular epithelial cells through activation of Smad pathway and induction of TGFB1
  • its expression identifies distinct connective tissue stem cells in both the bone (OCR stem cells) and the intestine (iRSCs)
  • functions as a regulator of survival, proliferation, migration, and invasion of fibroblast-like synoviocytes of rheumatoid arthritis (RA)
    text neurogenesis
    secreted antagonist of the bone morphogenetic protein (BMP) pathway
    a component
  • GREM1/KDR axis participates in renal inflammation and could be a novel target for kidney disease
    small molecule
  • interacted with YWHAH (YWHAH binding site for gremlin 1 was located between AAs 61-80 and gremlin 1 binding site for YWHAH was found to be located between residues 1 to 67)
  • interacting with BMP4 (BMP4 and Gremlin, which are highly expressed by fetal skeletal muscle side population and main population cells, respectively, are regulators of myogenic progenitor proliferation)
  • binds bone morphogenetic proteins (BMPs) 2, 4, and 7, antagonizing their actions
  • inhibits BMP signaling through BMPR1A (ALK3), BMPR1B (ALK6) or ACVR1 (ALK2) to SMAD1, SMAD5 or SMAD8
  • bone morphogenetic protein (BMP) antagonist whose upregulation blocks BMP2, BMP4 and BMP7
  • GREM1 also induces both TGFB2 and CTGF, which can act downstream to mediate some of these ECM changes in trabecular meshwork (TM)cells
  • TWIST2 regulates early limb morphogenesis through a role in terminating the SHH/GREM1/FGF autoregulatory loop
  • differential regulation of GREM1 and GREM2 gene expressions by BMP2 may explain the critical function of these genes during osteoblast differentiation
  • directly, by a TGFB1 independent process, activates the Smad pathway
  • GREM1 preferentially binds to BMP2 and this may be the dominant complex in a disease situation where levels of GREM1 and BMPs are elevated
  • binds to vascular endothelial growth factor receptor-2 (KDR) in endothelial cells to induce angiogenesis
  • cell & other
    Other regulated by SHH
    corresponding disease(s)
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral     --low  
    associated with tumor progression
    tumoral     --other  
    aberrantly expressed by cancer-associated stromal cells (basal cell carcinoma)
    constitutional     --over  
    overexpression causes osteopenia
    constitutional   deletion    
    causes increased trabecular bone volume secondary to increased bone formation and osteoblastic activity
    constitutional   deletion    
    has a major impact in the early phases of bone acquisition, and are in accordance with the role of BMPs during skeletal development
    tumoral     --low  
    by hypermethylation in renal cell carcinoma
    constitutional germinal mutation      
    in isolated Congenital anomalies of the kidney and urinary tract (CAKUT)
    constitutional     --over  
    in rheumatoid arthritis (RA) joints
    Susceptibility to colorectal cancer (CRC)
    Variant & Polymorphism other SNPs near GREM1 were strongly associated with increased CRC risk
    Candidate gene
    Therapy target
    neurosensorialvisualanterior chamber
    modulation of the extracellular matrix via gremlin provides a novel therapeutic target for glaucoma