Gremlin (protein)

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.

gremlin 1, cysteine knot superfamily, homolog (Xenopus laevis)
Identifiers
SymbolGREM1
Alt. symbolsCKTSF1B1
NCBI gene26585
HGNC2001
OMIM603054
RefSeqNM_013372
UniProtO60565
Other data
LocusChr. 15 q11-13
gremlin 2, cysteine knot superfamily, homolog (Xenopus laevis)
Identifiers
SymbolGREM2
NCBI gene64388
HGNC17655
OMIM608832
RefSeqNM_022469
UniProtQ9H772
Other data
LocusChr. 1 q43

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]

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.[11] 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][12] 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.[12]

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.[13] 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.[12]

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.[14] There are additional CRMs that regulate Grem1 transcription.[15]

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References
  1. 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. 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. PMID 17077323.
  3. 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. doi:10.1038/44157. PMID 10524628.
  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. doi:10.1126/science.1168755. PMID 19229034.
  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.
  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.
  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.
  11. 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. doi:10.1073/pnas.0606857103. PMC 1578503. PMID 17003113.
  12. 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.
  13. 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
  14. 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
  15. 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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