Selected-GenAtlas references	SOURCE	GeneCards	NCBI Gene	Swiss-Prot	Ensembl
	HGNC	UniGene	Nucleotide	OMIM	UCSC

Home Page

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

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

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

DNA

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

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_013372 2 - 4175 NP_037504 - 184 - 2008 18545679

EXPRESSION

Type

widely

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Digestive mouth       highly   stomach       highly Nervous brain         Reproductive female system ovary       Visual eye retina

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Connective cartilage     highly Nervous central       Nervous peripherous

cells

System Cell Pubmed Species Stage Rna symbol Nervous astrocyte Nervous neuron not specific chondrocyte Visual rod photoreceptor

cell lineage

cell lines

fluid/secretion

at STAGE

physiological period

embryo, fetal

Text	brain, neural crest, trabecular meshwork

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)

Type Gene Modification Chromosome rearrangement Protein expression Protein 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
	System Type Disorder Pubmed neurosensorial visual anterior chamber modulation of the extracellular matrix via gremlin provides a novel therapeutic target for glaucoma

ANIMAL & CELL MODELS