Gremlin is an

inhibitor Inhibitor or inhibition may refer to: In 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 neurotra ...

in the

TGF beta signaling pathway The transforming growth factor beta (TGFB) 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 an ...

. 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 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 as glyco ...

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. Originally discovered by their ability to induce the formation of bone and cartilage, BMPs are now considered to constitute a group of p ...

(BMPs) in the

. Grem1 inhibits predominantly BMP2 and BMP4 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 macrophages; they are involved in a wide variety of processes, most notably as crucial elements for normal development in animal cells. Any irregularities in their ...

(FGFs) 4 and 8 and

sonic hedgehog Sonic hedgehog protein (SHH) is encoded for by the ''SHH'' gene. The protein is named after the character ''Sonic the Hedgehog''. This signaling molecule is key in regulating embryonic morphogenesis in all animals. SHH controls organogenesis a ...

(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 ...

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 genes from a sample (e.g. from a tissue). It is a two-dimensional array on a solid substrate—usually a glass slide or silicon ...

of cancer and non-cancer tissues suggest that grem1 and other BMP antagonists are important in the survival of cancer 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 malignant tumor, a type of cancer that arises from transformed cells of mesenchymal ( connective tissue) origin. Connective tissue is a broad term that includes bone, cartilage, fat, vascular, or hematopoietic tissues, and sar ...

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, mesoderm ...

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 A binding protein is any protein that acts as an agent to bind two or more molecules together. Examples include: * DNA-binding protein ** Single-strand binding protein ** Telomere-binding protein *RNA-binding protein ** Poly(A)-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 by processes of sprouting and splittin ...

endothelium The endothelium 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 rest of the ve ...

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 (plural trabeculae, from Latin for "small beam") is a small, often microscopic, tissue element in the form of a small beam, strut or rod that supports or anchors a framework of parts within a body or organ. A trabecula generally ha ...

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 osteop ...

. 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 language, Greek combining forms for "bone", ὀστέο-, ''osteo-'' and βλαστάνω, ''blastanō'' "germinate") are cell (biology), cells with a single Cell nucleus, nucleus that synthesize bone. However, in the p ...

differentiation or the inhibition of bone formation and the ability for

bone remodeling Bone remodeling (or bone metabolism) is a lifelong process where mature bone tissue is removed from the skeleton (a process called ''bone resorption'') and new bone tissue is formed (a process called ''ossification'' or ''new bone formation''). ...

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

polydactyly Polydactyly or polydactylism (), also known as hyperdactyly, is an anomaly in humans and animals resulting in supernumerary fingers and/or toes. Polydactyly is the opposite of oligodactyly (fewer fingers or toes). Signs and symptoms In hum ...

. 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 beta-catenin (β-catenin), is a protein that in humans is encoded by the ''CTNNB1'' gene. Beta-catenin is a dual function protein, involved in regulation and coordination of cell–cell adhesion and gene transcrip ...

signaling activity. The interaction between Grem1 and the

Wnt signaling pathway 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 is a portmanteau created from the names Wingless and Int-1. Wnt signaling ...

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 morphogen ...

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