Gremlin (protein)
gremlin 1, cysteine knot superfamily, homolog (Xenopus laevis) | |||||||
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Identifiers | |||||||
Symbol | GREM1 | ||||||
Alt. symbols | CKTSF1B1 | ||||||
Chr. 15 q11-13 | |||||||
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gremlin 2, cysteine knot superfamily, homolog (Xenopus laevis) | |||||||
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Identifiers | |||||||
Symbol | GREM2 | ||||||
Chr. 1 q43 | |||||||
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Gremlin is an inhibitor in the TGF beta signaling pathway. 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 part of the DAN family and is a cysteine knot-secreted protein.[1][2] Gremlin1 was first identified in differential screening as a transcriptional down-regulated gene in v-mos-transformed rat embryonic fibroblasts.[3]
Function
Gremlin1 (Grem1) is known for its antagonistic interaction with
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 (VEGF). Both molecules are capable of binding to the VEGF receptor to activate vascular differentiation and proliferation during development.[11] 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. [12]
Clinical significance
Cancer
Data from microarrays 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.[13] 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 carcinomas. More specifically, the Grem1 binding site (between residues 1 to 67) interacts with the binding protein YWHAH, (whose binding site for Grem1 is between residues 61-80) and is seen as a potential therapeutic and diagnostic target against human cancers.[3]
Grem1 also plays a BMP-dependent role in angiogenesis on endothelium of human lung tissue, which implies a role for Grem1 in the development of cancer.[2]
Bone
Deletion of Grem1 in mice after birth increased bone formation and increased trabecular bone volume, whereas overexpression causes inhibition of bone formation and osteopenia.[1][14] 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.[14]
Grem1 plays an important role in
Transcriptional regulation
References
- ^ PMID 15539560.
- ^ PMID 17077323.
- ^ PMID 16545136.
- S2CID 4372393.
- PMID 15198975.
- S2CID 25309127.
- S2CID 19761724.
- PMID 15201225.
- S2CID 7867216.
- S2CID 16350339.
- PMID 35203511.
- PMID 31700227.
- PMID 17003113.
- ^ PMID 17785465.
- ^ Jacqueline L. Norrie, Jordan P. Lewandowski, Cortney M. Bouldin, Smita Amarnath, Qiang Li, Martha S. Vokes, Lauren I.R. Ehrlich, Brian D. Harfe, Steven A. Vokes. Dynamics of BMP signaling in limb bud mesenchyme and polydactyly (2014) Developmental Biology Volume 393, Issue 2, Pages 270–281
- ^ Li, Q., Lewandowski, J. P., Powell, M. B., Norrie, J. L., Cho, S. H. and Vokes, S. a (2014). A Gli silencer is required for robust repression of gremlin in the vertebrate limb bud. Development 141, 1906–14
- ^ 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
External links
- GREM1+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- GREM2+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)