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FLASH GENE
Symbol GREM1 contributors: mct/npt/pgu - updated : 27-08-2015
HGNC name gremlin 1, cysteine knot superfamily, homolog (Xenopus laevis)
HGNC id 2001
PROTEIN
PHYSICAL PROPERTIES
STRUCTURE
motifs/domains
  • C terminal cystein Knot-like domain
    • conjugated GlycoP
    HOMOLOGY
    interspecies homolog to Xenopus dorsalizing factor Gremlin
    homolog to Drosophila drumstick
    Homologene
    FAMILY
  • cysteine knot superfamily
  • DAN family of secreted bone morphogenetic protein (BMP) antagonists
    • CATEGORY tumor suppressor
    SUBCELLULAR LOCALIZATION extracellular
    text
  • 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)
    • CELLULAR PROCESS
    PHYSIOLOGICAL PROCESS development
    text neurogenesis
    PATHWAY
    metabolism
    signaling
    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
    • INTERACTION
    DNA
    RNA
    small molecule
    protein
  • 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
    REGULATION
    Other regulated by SHH
    ASSOCIATED DISORDERS
    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
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    neurosensorialvisualanterior chamber
    modulation of the extracellular matrix via gremlin provides a novel therapeutic target for glaucoma
    ANIMAL & CELL MODELS