Gremlin (protein)

Last updated
gremlin 1, cysteine knot superfamily, homolog (Xenopus laevis)
Identifiers
SymbolGREM1
Alt. symbolsCKTSF1B1
NCBI gene 26585
HGNC 2001
OMIM 603054
RefSeq NM_013372
UniProt O60565
Other data
Locus Chr. 15 q11-13
Search for
Structures Swiss-model
Domains InterPro
gremlin 2, cysteine knot superfamily, homolog (Xenopus laevis)
Identifiers
SymbolGREM2
NCBI gene 64388
HGNC 17655
OMIM 608832
RefSeq NM_022469
UniProt Q9H772
Other data
Locus Chr. 1 q43
Search for
Structures Swiss-model
Domains InterPro

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.

Contents

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 bone morphogenetic proteins (BMPs) in the TGF beta signaling pathway. 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. [4] [5] [6] Inhibition of BMPs by Grem1 in limb buds allows the transcriptional up-regulation of the fibroblast growth factors (FGFs) 4 and 8 and sonic hedgehog (SHH) ligands, which are part of the signaling system that controls progression of limb bud development. [7] [8] Grem1 regulation of BMP4 in mice embryos is also essential for kidney and lung branching morphogenesis. [9] [10]

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 bone development and a lesser known function later in adulthood. Overexpression of Grem1 decreases osteoblast differentiation or the inhibition of bone formation and the ability for bone remodeling. [1] In addition, overexpression of Grem1 in the mouse limb bud inhibits BMP signaling which can lead to digit loss as well as polydactyly. [15] Overexpression of grem1 in stromal and osteoblastic cells in addition to the inhibition of BMP, grem 1 inhibits activation of Wnt/β-catenin signaling activity. The interaction between Grem1 and the Wnt signaling pathway is not fully understood. [14]

Transcriptional regulation

Cis-regulatory modules (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. [16] There are additional CRMs that regulate Grem1 transcription. [17]

Related Research Articles

<span class="mw-page-title-main">Sonic hedgehog protein</span> Signaling molecule in animals

Sonic hedgehog protein (SHH) is encoded for by the SHH gene. The protein is named after the video game character Sonic the Hedgehog.

<span class="mw-page-title-main">Paracrine signaling</span> Form of localized cell signaling

In cellular biology, paracrine signaling is a form of cell signaling, a type of cellular communication in which a cell produces a signal to induce changes in nearby cells, altering the behaviour of those cells. Signaling molecules known as paracrine factors diffuse over a relatively short distance, as opposed to cell signaling by endocrine factors, hormones which travel considerably longer distances via the circulatory system; juxtacrine interactions; and autocrine signaling. Cells that produce paracrine factors secrete them into the immediate extracellular environment. Factors then travel to nearby cells in which the gradient of factor received determines the outcome. However, the exact distance that paracrine factors can travel is not certain.

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 pivotal morphogenetic signals, orchestrating tissue architecture throughout the body. The important functioning of BMP signals in physiology is emphasized by the multitude of roles for dysregulated BMP signalling in pathological processes. Cancerous disease often involves misregulation of the BMP signalling system. Absence of BMP signalling is, for instance, an important factor in the progression of colon cancer, and conversely, overactivation of BMP signalling following reflux-induced esophagitis provokes Barrett's esophagus and is thus instrumental in the development of esophageal adenocarcinoma.

<span class="mw-page-title-main">GLI2</span> Protein-coding gene in the species Homo sapiens

Zinc finger protein GLI2 also known as GLI family zinc finger 2 is a protein that in humans is encoded by the GLI2 gene. The protein encoded by this gene is a transcription factor.

<span class="mw-page-title-main">GLI3</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">Bone morphogenetic protein 4</span> Human protein and coding gene

Bone morphogenetic protein 4 is a protein that in humans is encoded by BMP4 gene. BMP4 is found on chromosome 14q22-q23.

<span class="mw-page-title-main">Bone morphogenetic protein 6</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">Bone morphogenetic protein 3</span> Protein-coding gene in the species Homo sapiens

Bone morphogenetic protein 3, also known as osteogenin, is a protein in humans that is encoded by the BMP3 gene.

<span class="mw-page-title-main">BMPR1A</span> Bone morphogenetic protein receptor

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<span class="mw-page-title-main">Apical ectodermal ridge</span>

The apical ectodermal ridge (AER) is a structure that forms from the ectodermal cells at the distal end of each limb bud and acts as a major signaling center to ensure proper development of a limb. After the limb bud induces AER formation, the AER and limb mesenchyme—including the zone of polarizing activity (ZPA)—continue to communicate with each other to direct further limb development.

<span class="mw-page-title-main">Limb development</span>

Limb development in vertebrates is an area of active research in both developmental and evolutionary biology, with much of the latter work focused on the transition from fin to limb.

The limb bud is a structure formed early in vertebrate limb development. As a result of interactions between the ectoderm and underlying mesoderm, formation occurs roughly around the fourth week of development. In the development of the human embryo the upper limb bud appears in the third week and the lower limb bud appears four days later.

<span class="mw-page-title-main">GDF6</span> Protein-coding gene in the species Homo sapiens

Growth differentiation factor 6 (GDF6) is a protein that in humans is encoded by the GDF6 gene.

<span class="mw-page-title-main">Cerberus (protein)</span> Protein found in humans

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<span class="mw-page-title-main">Fibroblast growth factor 8</span> Protein-coding gene in the species Homo sapiens

Fibroblast growth factor 8(FGF-8) is a protein that in humans is encoded by the FGF8 gene.

<span class="mw-page-title-main">TBX2</span> Protein-coding gene in the species Homo sapiens

T-box transcription factor 2 Tbx2 is a transcription factor that is encoded by the Tbx2 gene on chromosome 17q21-22 in humans. This gene is a member of a phylogenetically conserved family of genes that share a common DNA-binding domain, the T-box. Tbx2 and Tbx3 are the only T-box transcription factors that act as transcriptional repressors rather than transcriptional activators, and are closely related in terms of development and tumorigenesis. This gene plays a significant role in embryonic and fetal development through control of gene expression, and also has implications in various cancers. Tbx2 is associated with numerous signaling pathways, BMP, TGFβ, Wnt, and FGF, which allow for patterning and proliferation during organogenesis in fetal development.

<span class="mw-page-title-main">Zone of polarizing activity</span>

The zone of polarizing activity (ZPA) is an area of mesenchyme that contains signals which instruct the developing limb bud to form along the anterior/posterior axis. Limb bud is undifferentiated mesenchyme enclosed by an ectoderm covering. Eventually, the limb bud develops into bones, tendons, muscles and joints. Limb bud development relies not only on the ZPA, but also many different genes, signals, and a unique region of ectoderm called the apical ectodermal ridge (AER). Research by Saunders and Gasseling in 1948 identified the AER and its subsequent involvement in proximal distal outgrowth. Twenty years later, the same group did transplantation studies in chick limb bud and identified the ZPA. It wasn't until 1993 that Todt and Fallon showed that the AER and ZPA are dependent on each other.

Within molecular and cell biology, temporal feedback, also referred to as interlinked or interlocked feedback, is a biological regulatory motif in which fast and slow positive feedback loops are interlinked to create "all or none" switches. This interlinking produces separate, adjustable activation and de-activation times. This type of feedback is thought to be important in cellular processes in which an "all or none" decision is a necessary response to a specific input. The mitotic trigger, polarization in budding yeast, mammalian calcium signal transduction, EGF receptor signaling, platelet activation, and Xenopus oocyte maturation are examples for interlinked fast and slow multiple positive feedback systems.

References

  1. 1 2 3 Gazzerro E, Pereira RC, Jorgetti V, Olson S, Economides AN, Canalis E (2005). "Skeletal overexpression of gremlin impairs bone formation and causes osteopenia". Endocrinology. 146 (2): 655–65. doi: 10.1210/en.2004-0766 . PMID   15539560.
  2. 1 2 Stabile H, Mitola S, Moroni E, Belleri M, Nicoli S, Coltrini D, Peri F, Pessi A, Orsatti L, Talamo F, Castronovo V, Waltregny D, Cotelli F, Ribatti D, Presta M (2007). "Bone morphogenic protein antagonist Drm/gremlin is a novel proangiogenic factor". Blood. 109 (5): 1834–40. doi: 10.1182/blood-2006-06-032276 . hdl: 11379/29323 . PMID   17077323.
  3. 1 2 Namkoong H, Shin SM, Kim HK, Ha SA, Cho GW, Hur SY, Kim TE, Kim JW (2006). "The bone morphogenetic protein antagonist gremlin 1 is overexpressed in human cancers and interacts with YWHAH protein". BMC Cancer. 6: 74. doi: 10.1186/1471-2407-6-74 . PMC   1459871 . PMID   16545136.
  4. ↑ Zúñiga A, Haramis AP, McMahon AP, Zeller R (1999). "Signal relay by BMP antagonism controls the SHH/FGF4 feedback loop in vertebrate limb buds". Nature. 401 (6753): 598–602. Bibcode:1999Natur.401..598Z. doi:10.1038/44157. PMID   10524628. S2CID   4372393.
  5. ↑ Zuniga A, Michos O, Spitz F, Haramis AP, Panman L, Galli A, Vintersten K, Klasen C, Mansfield W, Kuc S, Duboule D, Dono R, Zeller R (2004). "Mouse limb deformity mutations disrupt a global control region within the large regulatory landscape required for Gremlin expression". Genes Dev. 18 (13): 1553–64. doi:10.1101/gad.299904. PMC   443518 . PMID   15198975.
  6. ↑ Bénazet JD, Bischofberger M, Tiecke E, Gonçalves A, Martin JF, Zuniga A, Naef F, Zeller R (2009). "A self-regulatory system of interlinked signaling feedback loops controls mouse limb patterning". Science. 323 (5917): 1050–3. Bibcode:2009Sci...323.1050B. doi:10.1126/science.1168755. PMID   19229034. S2CID   25309127.
  7. ↑ Khokha MK, Hsu D, Brunet LJ, Dionne MS, Harland RM (2003). "Gremlin is the BMP antagonist required for maintenance of Shh and Fgf signals during limb patterning". Nat. Genet. 34 (3): 303–7. doi:10.1038/ng1178. PMID   12808456. S2CID   19761724.
  8. ↑ Michos O, Panman L, Vintersten K, Beier K, Zeller R, Zuniga A (2004). "Gremlin-mediated BMP antagonism induces the epithelial-mesenchymal feedback signaling controlling metanephric kidney and limb organogenesis". Development. 131 (14): 3401–10. doi: 10.1242/dev.01251 . PMID   15201225.
  9. ↑ Michos O, Gonçalves A, Lopez-Rios J, Tiecke E, Naillat F, Beier K, Galli A, Vainio S, Zeller R (2007). "Reduction of BMP4 activity by gremlin 1 enables ureteric bud outgrowth and GDNF/WNT11 feedback signalling during kidney branching morphogenesis". Development. 134 (13): 2397–405. doi:10.1242/dev.02861. PMID   17522159. S2CID   7867216.
  10. ↑ Shi W, Zhao J, Anderson KD, Warburton D (2001). "Gremlin negatively modulates BMP-4 induction of embryonic mouse lung branching morphogenesis". Am. J. Physiol. Lung Cell Mol. Physiol. 280 (5): L1030–9. doi:10.1152/ajplung.2001.280.5.L1030. PMID   11290528. S2CID   16350339.
  11. ↑ Elemam NM, Malek AI, Mahmoud EE, El-Huneidi W, Talaat IM (2022-01-28). "Insights into the Role of Gremlin-1, a Bone Morphogenic Protein Antagonist, in Cancer Initiation and Progression". Biomedicines. 10 (2): 301. doi: 10.3390/biomedicines10020301 . ISSN   2227-9059. PMC   8869528 . PMID   35203511.
  12. ↑ Li D, Yuan D, Shen H, Mao X, Yuan S, Liu Q (2019-10-21). "Gremlin-1: An endogenous BMP antagonist induces epithelial-mesenchymal transition and interferes with redifferentiation in fetal RPE cells with repeated wounds". Molecular Vision. 25: 625–635. ISSN   1090-0535. PMC   6817737 . PMID   31700227.
  13. ↑ Sneddon JB, Zhen HH, Montgomery K, van de Rijn M, Tward AD, West R, Gladstone H, Chang HY, Morganroth GS, Oro AE, Brown PO (2006). "Bone morphogenetic protein antagonist gremlin 1 is widely expressed by cancer-associated stromal cells and can promote tumor cell proliferation". Proc. Natl. Acad. Sci. U.S.A. 103 (40): 14842–7. Bibcode:2006PNAS..10314842S. doi: 10.1073/pnas.0606857103 . PMC   1578503 . PMID   17003113.
  14. 1 2 3 Gazzerro E, Smerdel-Ramoya A, Zanotti S, Stadmeyer L, Durant D, Economides AN, Canalis E (2007). "Conditional deletion of gremlin causes a transient increase in bone formation and bone mass". J. Biol. Chem. 282 (43): 31549–57. doi: 10.1074/jbc.M701317200 . PMID   17785465.
  15. ↑ 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
  16. ↑ 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
  17. ↑ 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
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