Gremlin is an

inhibitor Inhibitor or inhibition may refer to: Biology * Enzyme inhibitor, a substance that binds to an enzyme and decreases the enzyme's activity * Reuptake inhibitor, a substance that increases neurotransmission by blocking the reuptake of a neurotransmi ...

in the

TGF beta signaling pathway The transforming growth factor beta (TGFβ) signaling pathway is involved in many cellular processes in both the adult organism and the developing embryo including cell growth, cell differentiation, cell migration, apoptosis, cellular homeostasis a ...

. It primarily inhibits bone morphogenesis and is implicated in disorders of increased bone formation and several cancers.

Structure

Gremlin1, previously known as Drm, is a highly conserved 20.7-kDa, 184 amino acid

glycoprotein Glycoproteins are proteins which contain oligosaccharide (sugar) chains covalently attached to amino acid side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known a ...

part of the DAN family and is a cysteine knot-secreted protein. Gremlin1 was first identified in differential screening as a transcriptional down-regulated gene in v-mos-transformed rat embryonic fibroblasts.

Function

Gremlin1 (Grem1) is known for its antagonistic interaction with

bone morphogenetic proteins Bone morphogenetic proteins (BMPs) are a group of growth factors also known as cytokines and as metabologens. Professor Marshall R. Urist, Marshall Urist and Professor A. Hari Reddi, Hari Reddi discovered their ability to induce the formation of b ...

(BMPs) in the

. Grem1 inhibits predominantly BMP2 and

BMP4 Bone morphogenetic protein 4 is a protein that in humans is encoded by ''BMP4'' gene. BMP4 is found on chromosome 14q22-q23. BMP4 is a member of the bone morphogenetic protein family which is part of the transforming growth factor-beta superfami ...

in limb buds and functions as part of a self-regulatory feedback signaling system, which is essential for normal limb bud development and digit formation. Inhibition of BMPs by Grem1 in limb buds allows the transcriptional up-regulation of the

fibroblast growth factors Fibroblast growth factors (FGF) are a family of cell signalling proteins produced by the macrophages. They are involved in a wide variety of processes, most notably as crucial elements for normal development in animal cells. Any irregularities in ...

(FGFs) 4 and 8 and

sonic hedgehog Sonic hedgehog protein (SHH) is a major signaling molecule of embryonic development in humans and animals, encoded by the ''SHH'' gene. This signaling molecule is key in regulating embryonic morphogenesis in all animals. SHH controls organoge ...

(SHH) ligands, which are part of the signaling system that controls progression of limb bud development. Grem1 regulation of BMP4 in mice embryos is also essential for kidney and lung branching

morphogenesis Morphogenesis (from the Greek ''morphê'' shape and ''genesis'' creation, literally "the generation of form") is the biological process that causes a cell, tissue or organism to develop its shape. It is one of three fundamental aspects of deve ...

Fetal Development

While GREM1 functions as a BMP antagonist during limb bud formation, it also functions as a pro-angiogenic molecule. As stated above, GREM1 is a member of the cysteine-knot superfamily similar to

vascular endothelial growth factor Vascular endothelial growth factor (VEGF, ), originally known as vascular permeability factor (VPF), is a signal protein produced by many cells that stimulates the formation of blood vessels. To be specific, VEGF is a sub-family of growth factors ...

(VEGF). Both molecules are capable of binding to the VEGF receptor to activate vascular differentiation and proliferation during development. In the absence of GREM1, it is possible to see unregulated bone growth as there is no inhibitory signal to regulate the bone morphogenetic proteins. Gremlin1 also plays a role in the epithelial-mesenchymal transition (EMT). Although this is an important process for neural tube development and other fetal structures, it is also a necessary process for tumor metastasis as it can activate the TGF beta pathway in the event of an overexpression of GREM1. This has made GREM1 the proposed target for cancer therapeutics, however, more research is necessary before any major steps are taken.

Clinical significance

Cancer

Data from

microarrays A microarray is a multiplex lab-on-a-chip. Its purpose is to simultaneously detect the expression of thousands of biological interactions. It is a two-dimensional array on a solid substrate—usually a glass slide or silicon thin-film cell� ...

of cancer and non-cancer tissues suggest that grem1 and other BMP

antagonists An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain.stroma and proliferation in some cancers. Grem1 expression is found in many cancers and is thought to play important roles in uterine cervix, lung, ovary, kidney, breast, colon, pancreas, and

sarcoma A sarcoma is a rare type of cancer that arises from cells of mesenchymal origin. Originating from mesenchymal cells means that sarcomas are cancers of connective tissues such as bone, cartilage, muscle, fat, or vascular tissues. Sarcom ...

carcinoma Carcinoma is a malignancy that develops from epithelial cells. Specifically, a carcinoma is a cancer that begins in a tissue that lines the inner or outer surfaces of the body, and that arises from cells originating in the endodermal, mesoder ...

s. More specifically, the Grem1

binding site In biochemistry and molecular biology, a binding site is a region on a macromolecule such as a protein that binds to another molecule with specificity. The binding partner of the macromolecule is often referred to as a ligand. Ligands may includ ...

(between residues 1 to 67) interacts with the binding protein

YWHAH 14-3-3 protein eta also referred to as 14-3-3η is a protein that in humans is encoded by the ''YWHAH'' gene. Function This gene product belongs to the 14-3-3 family of proteins that are normally intracellular in nature and help to mediate si ...

, (whose binding site for Grem1 is between residues 61-80) and is seen as a potential therapeutic and diagnostic target against human cancers. Grem1 also plays a BMP-dependent role in

angiogenesis Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature mainly by processes of sprouting and ...

endothelium The endothelium (: endothelia) is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the r ...

of human lung tissue, which implies a role for Grem1 in the development of cancer.

Bone

Deletion of Grem1 in mice after birth increased bone formation and increased

trabecula A trabecula (: trabeculae, from Latin for 'small beam') is a small, often microscopic, biological tissue, tissue element in the form of a small Beam (structure), beam, strut or rod that supports or anchors a framework of parts within a body or ...

r bone volume, whereas overexpression causes inhibition of bone formation and

osteopenia Osteopenia, known as "low bone mass" or "low bone density", is a condition in which bone mineral density is low. Because their bones are weaker, people with osteopenia may have a higher risk of fractures, and some people may go on to develop o ...

. Conditional deletion of one copy of Grem1 does not produce an abnormal phenotype and deletion of both copies causes only a small difference in phenotype in one-month-old male mice, but this difference cannot be observed after 3 months of age. Grem1 plays an important role in bone development and a lesser known function later in adulthood. Overexpression of Grem1 decreases

osteoblast Osteoblasts (from the Greek combining forms for " bone", ὀστέο-, ''osteo-'' and βλαστάνω, ''blastanō'' "germinate") are cells with a single nucleus that synthesize bone. However, in the process of bone formation, osteoblasts fu ...

differentiation or the inhibition of bone formation and the ability for

bone remodeling 300 px, Bone tissue is removed by osteoclasts, and then new bone tissue is formed by osteoblasts. Both processes utilize cytokine ( Insulin-like_growth_factor.html" ;"title="TGF-β, Insulin-like growth factor">IGF) signalling. In osteology, bone ...

. In addition, overexpression of Grem1 in the mouse limb bud inhibits BMP signaling which can lead to digit loss as well as

polydactyly Polydactyly is a birth defect that results in extra fingers or toes. The hands are more commonly involved than the feet. Extra fingers may be painful, affect self-esteem, or result in clumsiness. It is associated with at least 39 genetic mut ...

. Overexpression of grem1 in stromal and osteoblastic cells in addition to the inhibition of BMP, grem 1 inhibits activation of Wnt/

β-catenin Catenin beta-1, also known as β-catenin (''beta''-catenin), is a protein that in humans is encoded by the ''CTNNB1'' gene. β-Catenin is a dual function protein, involved in regulation and coordination of cell–cell adhesion and gene transcr ...

signaling activity. The interaction between Grem1 and the

Wnt signaling pathway In cellular biology, the Wnt signaling pathways are a group of signal transduction pathways which begin with proteins that pass signals into a cell through cell surface receptors. The name Wnt, pronounced "wint", is a portmanteau created from the ...

is not fully understood.

Transcriptional regulation

Cis-regulatory module ''Cis''-regulatory elements (CREs) or ''cis''-regulatory modules (CRMs) are regions of non-coding DNA which regulate the transcription of neighboring genes. CREs are vital components of genetic regulatory networks, which in turn control morphog ...

s (CRMs) regulate when and where Grem1 is transcribed. It has been reported that a CRM acts as both a silencer and activator for Grem1 transcription in the mouse limb bud. There are additional CRMs that regulate Grem1 transcription.Zuniga, A., Laurent, F., Lopez-Rios, J., Klasen, C., Matt, N. and Zeller, R. (2012). Conserved cis-regulatory regions in a large genomic landscape control SHH and BMP-regulated Gremlin1 expression in mouse limb buds. BMC Dev. Biol. 12, 23

References

External links

* * {{TGFβ receptor superfamily modulators