GPR126

Last updated
ADGRG6
Identifiers
Aliases ADGRG6 , APG1, DREG, PS1TP2, VIGR, GPR126, LCCS9, adhesion G protein-coupled receptor G6, PR126
External IDs OMIM: 612243 MGI: 1916151 HomoloGene: 10724 GeneCards: ADGRG6
Orthologs
SpeciesHumanMouse
Entrez

57211

215798

Ensembl

ENSG00000112414

ENSMUSG00000039116

UniProt

Q86SQ4

Q6F3F9

RefSeq (mRNA)

NM_001032394
NM_001032395
NM_020455
NM_198569

NM_001002268

RefSeq (protein)

NP_001027566
NP_001027567
NP_065188
NP_940971

NP_001002268

Location (UCSC) Chr 6: 142.3 – 142.45 Mb Chr 10: 14.28 – 14.42 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

G protein-coupled receptor 126 also known as VIGR and DREG is a protein encoded by the ADGRG6 gene. [5] [6] [7] GPR126 is a member of the adhesion GPCR family. [8] [9] Adhesion GPCRs are characterized by an extended extracellular region often possessing N-terminal protein modules that is linked to a TM7 region via a domain known as the GPCR-Autoproteolysis INducing (GAIN) domain. [10]

Contents

GPR126 is all widely expressed on stromal cells. [11] The N-terminal fragment of GPR126 contains C1r-C1s, Uegf and Bmp1 (CUB), and PTX-like modules. [12]

Ligand

GPR126 was shown to bind collagen IV and laminin-211 promoting cyclic adenosine monophosphate (cAMP) to mediate myelination. [13] [14]

Signaling

Upon lipopolysaccharide (LPS) or thrombin stimulation, expression of GPR126 is induced by MAP kinases in endothelial cells. [12] During angiogenesis, GPR126 promotes protein kinase A (PKA)–cAMP-activated signaling in endothelial cells. [15] Forced GPR126 expression in COS-7 cells enhances cAMP levels by coupling to heterotrimeric Gαs/i proteins. [16]

Function

GPR126 has been identified in genomic regions associated with adult height, more specially trunk height, [17] [18] [19] pulmonary function [20] and adolescent idiopathic scoliosis. [21] In the vertebrate nervous system, many axons are surrounded by a myelin sheath to conduct action potentials rapidly and efficiently. Applying a genetic screen in zebrafish mutants, Talbot’s group demonstrated that GPR126 affects the development of myelinated axons. [22] GPR126 drives the differentiation of Schwann cells through inducing cAMP levels, which causes Oct6 transcriptional activities to promote myelin gene activity. [23] Mutation of gpr126 in zebrafish affects peripheral myelination. Monk’s group demonstrated domain-specific functions of GPR126 during Schwann cells development: the NTF is necessary and sufficient for axon sorting, while the CTF promotes wrapping through cAMP induction to regulate early and late stages of Schwann cells development. [14]

Outside of neurons, GPR126 function is required for heart and inner ear development. [24] [25] [26] GPR126 stimulates VEGF signaling and angiogenesis by modulating VEGF receptor 2 (VEGFR2) expression through STAT5 and GATA2 in endothelial cells. [15]

Disease

Mouse models have shown GPR126 deletion to affect cartilage biology and spinal column development, [27] supporting findings that variants of GPR126 have been associated with adolescent idiopathic scoliosis, [21] and Mutations have been shown to be responsible for severe arthrogryposis multiplex congenita [28]

Related Research Articles

In biochemistry, an orphan receptor is a protein that has a similar structure to other identified receptors but whose endogenous ligand has not yet been identified. If a ligand for an orphan receptor is later discovered, the receptor is referred to as an "adopted orphan". Conversely, the term orphan ligand refers to a biological ligand whose cognate receptor has not yet been identified.

<span class="mw-page-title-main">EMR1</span> Protein-coding gene in the species Homo sapiens

EGF-like module-containing mucin-like hormone receptor-like 1 also known as F4/80 is a protein encoded by the ADGRE1 gene. EMR1 is a member of the adhesion GPCR family. Adhesion GPCRs are characterized by an extended extracellular region often possessing N-terminal protein modules that is linked to a TM7 region via a domain known as the GPCR-Autoproteolysis INducing (GAIN) domain.

<span class="mw-page-title-main">EMR3</span> Protein-coding gene in the species Homo sapiens

EGF-like module-containing mucin-like hormone receptor-like 3 is a protein encoded by the ADGRE3 gene. EMR3 is a member of the adhesion GPCR family. Adhesion GPCRs are characterized by an extended extracellular region often possessing N-terminal protein modules that is linked to a TM7 region via a domain known as the GPCR-Autoproteolysis INducing (GAIN) domain.

<span class="mw-page-title-main">CD97</span> Mammalian protein found in Homo sapiens

Cluster of differentiation 97 is a protein also known as BL-Ac[F2] encoded by the ADGRE5 gene. CD97 is a member of the adhesion G protein-coupled receptor (GPCR) family. Adhesion GPCRs are characterized by an extended extracellular region often possessing N-terminal protein modules that is linked to a TM7 region via a domain known as the GPCR-Autoproteolysis INducing (GAIN) domain.

<span class="mw-page-title-main">GPR34</span> Protein-coding gene in humans

Probable G-protein coupled receptor 34 is a protein that in humans is encoded by the GPR34 gene.

<span class="mw-page-title-main">GPR65</span> Protein-coding gene in the species Homo sapiens

Psychosine receptor is a G protein-coupled receptor (GPCR) protein that in humans is encoded by the GPR65 gene. GPR65 is also referred to as TDAG8.

<span class="mw-page-title-main">GPR64</span> Protein-coding gene in humans

G protein-coupled receptor 64 also known as HE6 is a protein encoded by the ADGRG2 gene. GPR64 is a member of the adhesion GPCR family. Adhesion GPCRs are characterized by an extended extracellular region often possessing N-terminal protein modules that is linked to a TM7 region via a domain known as the GPCR-Autoproteolysis INducing (GAIN) domain.

<span class="mw-page-title-main">GPR124</span> Protein-coding gene in the species Homo sapiens

Probable G-protein coupled receptor 124 is a protein that in humans is encoded by the GPR124 gene. It is a member of the adhesion-GPCR family of receptors. Family members are characterized by an extended extracellular region with a variable number of protein domains coupled to a TM7 domain via a domain known as the GPCR-Autoproteolysis INducing (GAIN) domain.

<span class="mw-page-title-main">GPR123</span> Protein-coding gene in the species Homo sapiens

Probable G-protein coupled receptor 123 is a protein that in humans is encoded by the GPR123 gene. It is a member of the adhesion-GPCR family of receptors. Family members are normally characterized by an extended extracellular region with a variable number of protein domains coupled to a TM7 domain via a domain known as the GPCR-Autoproteolysis INducing (GAIN) domain.

<span class="mw-page-title-main">GPR128</span> Protein-coding gene in the species Homo sapiens

G protein-coupled receptor 128 is a protein encoded by the ADGRG7 gene. GPR128 is a member of the adhesion GPCR family. Adhesion GPCRs are characterized by an extended extracellular region often possessing N-terminal protein modules that is linked to a TM7 region via a domain known as the GPCR-Autoproteolysis INducing (GAIN) domain.

<span class="mw-page-title-main">GPR112</span> Protein-coding gene in humans

G protein-coupled receptor 112 is a protein encoded by the ADGRG4 gene. GPR112 is a member of the adhesion GPCR family. Adhesion GPCRs are characterized by an extended extracellular region often possessing N-terminal protein modules that is linked to a TM7 region via a domain known as the GPCR-Autoproteolysis INducing (GAIN) domain.

<span class="mw-page-title-main">GPR125</span> Protein-coding gene in the species Homo sapiens

Adhesion G-protein coupled receptor A3 (ADGRA3), also known as GPR125, is an adhesion GPCR that in humans is encoded by the Adgra3 gene.

<span class="mw-page-title-main">GPR114</span> Protein-coding gene in the species Homo sapiens

G protein-coupled receptor 114 is a protein encoded by the ADGRG5 gene. GPR114 is a member of the adhesion GPCR family. Adhesion GPCRs are characterized by an extended extracellular region often possessing N-terminal protein modules that is linked to a TM7 region via a domain known as the GPCR-Autoproteolysis INducing (GAIN) domain.

<span class="mw-page-title-main">GPR97</span> Protein-coding gene in the species Homo sapiens

G-protein coupled receptor 97 also known as adhesion G protein-coupled receptor G3 (ADGRG3) is a protein that in humans is encoded by the ADGRG3 gene. GPR97 is a member of the adhesion GPCR family. Adhesion GPCRs are characterized by an extended extracellular region often possessing N-terminal protein modules that is linked to a TM7 region via a domain known as the GPCR-Autoproteolysis INducing (GAIN) domain.

<span class="mw-page-title-main">GPR110</span> Protein-coding gene in the species Homo sapiens

Probable G-protein coupled receptor 110 is a protein that in humans is encoded by the GPR110 gene. This gene encodes a member of the adhesion-GPCR receptor family. Family members are characterized by an extended extracellular region with a variable number of N-terminal protein modules coupled to a TM7 region via a domain known as the GPCR-Autoproteolysis INducing (GAIN) domain.

<span class="mw-page-title-main">GPR133</span> Protein-coding gene in the species Homo sapiens

Probable G-protein coupled receptor 133 is a protein that in humans is encoded by the GPR133 gene.

<span class="mw-page-title-main">GPR144</span> Protein-coding gene in the species Homo sapiens

Probable G-protein coupled receptor 144 is a protein that in humans is encoded by the GPR144 gene. This gene encodes a member of the adhesion-GPCR family of receptors. Family members are characterised by an extended extracellular region with a variable number of protein domains coupled to a TM7 domain via a domain known as the GPCR-Autoproteolysis INducing (GAIN) domain.

<span class="mw-page-title-main">GPR56</span> Protein-coding gene in the species Homo sapiens

G protein-coupled receptor 56 also known as TM7XN1 is a protein encoded by the ADGRG1 gene. GPR56 is a member of the adhesion GPCR family. Adhesion GPCRs are characterized by an extended extracellular region often possessing N-terminal protein modules that is linked to a TM7 region via a domain known as the GPCR-Autoproteolysis INducing (GAIN) domain.

Secretin receptor family consists of secretin receptors regulated by peptide hormones from the glucagon hormone family. The family is different from adhesion G protein-coupled receptors.

<span class="mw-page-title-main">Adhesion G protein-coupled receptor</span> Class of 33 human protein receptors

Adhesion G protein-coupled receptors are a class of 33 human protein receptors with a broad distribution in embryonic and larval cells, cells of the reproductive tract, neurons, leukocytes, and a variety of tumours. Adhesion GPCRs are found throughout metazoans and are also found in single-celled colony forming choanoflagellates such as Monosiga brevicollis and unicellular organisms such as Filasterea. The defining feature of adhesion GPCRs that distinguishes them from other GPCRs is their hybrid molecular structure. The extracellular region of adhesion GPCRs can be exceptionally long and contain a variety of structural domains that are known for the ability to facilitate cell and matrix interactions. Their extracellular region contains the membrane proximal GAIN domain. Crystallographic and experimental data has shown this structurally conserved domain to mediate autocatalytic processing at a GPCR-proteolytic site (GPS) proximal to the first transmembrane helix. Autocatalytic processing gives rise to an extracellular (α) and a membrane-spanning (β) subunit, which are associated non-covalently, resulting in expression of a heterodimeric receptor at the cell surface. Ligand profiles and in vitro studies have indicated a role for adhesion GPCRs in cell adhesion and migration. Work utilizing genetic models confined this concept by demonstrating that the primary function of adhesion GPCRs may relate to the proper positioning of cells in a variety of organ systems. Moreover, growing evidence implies a role of adhesion GPCRs in tumour cell metastasis. Formal G protein-coupled signalling has been demonstrated for a number for adhesion GPCRs, however, the orphan receptor status of many of the receptors still hampers full characterisation of potential signal transduction pathways. In 2011, the adhesion GPCR consortium was established to facilitate research of the physiological and pathological functions of adhesion GPCRs.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000112414 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000039116 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ Fredriksson R, Gloriam DE, Höglund PJ, Lagerström MC, Schiöth HB (February 2003). "There exist at least 30 human G-protein-coupled receptors with long Ser/Thr-rich N-termini". Biochemical and Biophysical Research Communications. 301 (3): 725–34. doi:10.1016/S0006-291X(03)00026-3. PMID   12565841.
  6. ↑ "Entrez Gene: GPR126 G protein-coupled receptor 126".
  7. ↑ Hamann J, Aust G, Araç D, Engel FB, Formstone C, Fredriksson R, Hall RA, Harty BL, Kirchhoff C, Knapp B, Krishnan A, Liebscher I, Lin HH, Martinelli DC, Monk KR, Peeters MC, Piao X, Prömel S, Schöneberg T, Schwartz TW, Singer K, Stacey M, Ushkaryov YA, Vallon M, Wolfrum U, Wright MW, Xu L, Langenhan T, Schiöth HB (April 2015). "International Union of Basic and Clinical Pharmacology. XCIV. Adhesion G protein-coupled receptors". Pharmacological Reviews. 67 (2): 338–67. doi:10.1124/pr.114.009647. PMC   4394687 . PMID   25713288.
  8. ↑ Stacey M, Yona S (2011). Adhesion-GPCRs: Structure to Function (Advances in Experimental Medicine and Biology). Berlin: Springer. ISBN   978-1-4419-7912-4.
  9. ↑ Langenhan T, Aust G, Hamann J (May 2013). "Sticky signaling--adhesion class G protein-coupled receptors take the stage". Science Signaling. 6 (276): re3. doi:10.1126/scisignal.2003825. PMID   23695165. S2CID   6958640.
  10. ↑ Araç D, Boucard AA, Bolliger MF, Nguyen J, Soltis SM, Südhof TC, Brunger AT (March 2012). "A novel evolutionarily conserved domain of cell-adhesion GPCRs mediates autoproteolysis". The EMBO Journal. 31 (6): 1364–78. doi:10.1038/emboj.2012.26. PMC   3321182 . PMID   22333914.
  11. ↑ Hamann J, Aust G, Araç D, Engel FB, Formstone C, Fredriksson R, Hall RA, Harty BL, Kirchhoff C, Knapp B, Krishnan A, Liebscher I, Lin HH, Martinelli DC, Monk KR, Peeters MC, Piao X, Prömel S, Schöneberg T, Schwartz TW, Singer K, Stacey M, Ushkaryov YA, Vallon M, Wolfrum U, Wright MW, Xu L, Langenhan T, Schiöth HB (Apr 2015). "International Union of Basic and Clinical Pharmacology. XCIV. Adhesion G protein-coupled receptors". Pharmacological Reviews. 67 (2): 338–67. doi:10.1124/pr.114.009647. PMC   4394687 . PMID   25713288.
  12. 1 2 Stehlik C, Kroismayr R, Dorfleutner A, Binder BR, Lipp J (July 2004). "VIGR--a novel inducible adhesion family G-protein coupled receptor in endothelial cells". FEBS Letters. 569 (1–3): 149–55. doi:10.1016/j.febslet.2004.05.038. PMID   15225624. S2CID   13145438.
  13. ↑ Paavola KJ, Sidik H, Zuchero JB, Eckart M, Talbot WS (August 2014). "Type IV collagen is an activating ligand for the adhesion G protein-coupled receptor GPR126". Science Signaling. 7 (338): ra76. doi:10.1126/scisignal.2005347. PMC   4159047 . PMID   25118328.
  14. 1 2 Petersen SC, Luo R, Liebscher I, Giera S, Jeong SJ, Mogha A, Ghidinelli M, Feltri ML, Schöneberg T, Piao X, Monk KR (February 2015). "The adhesion GPCR GPR126 has distinct, domain-dependent functions in Schwann cell development mediated by interaction with laminin-211". Neuron. 85 (4): 755–69. doi:10.1016/j.neuron.2014.12.057. PMC   4335265 . PMID   25695270.
  15. 1 2 Cui H, Wang Y, Huang H, Yu W, Bai M, Zhang L, Bryan BA, Wang Y, Luo J, Li D, Ma Y, Liu M (December 2014). "GPR126 protein regulates developmental and pathological angiogenesis through modulation of VEGFR2 receptor signaling". The Journal of Biological Chemistry. 289 (50): 34871–85. doi: 10.1074/jbc.M114.571000 . PMC   4263886 . PMID   25217645.
  16. ↑ Mogha A, Benesh AE, Patra C, Engel FB, Schöneberg T, Liebscher I, Monk KR (November 2013). "Gpr126 functions in Schwann cells to control differentiation and myelination via G-protein activation". The Journal of Neuroscience. 33 (46): 17976–85. doi:10.1523/JNEUROSCI.1809-13.2013. PMC   3828454 . PMID   24227709.
  17. ↑ Gudbjartsson DF, Walters GB, Thorleifsson G, Stefansson H, Halldorsson BV, Zusmanovich P, et al. (May 2008). "Many sequence variants affecting diversity of adult human height". Nature Genetics. 40 (5): 609–15. doi:10.1038/ng.122. PMID   18391951. S2CID   3005450.
  18. ↑ Lettre G, Jackson AU, Gieger C, Schumacher FR, Berndt SI, Sanna S, et al. (May 2008). "Identification of ten loci associated with height highlights new biological pathways in human growth". Nature Genetics. 40 (5): 584–91. doi:10.1038/ng.125. PMC   2687076 . PMID   18391950.
  19. ↑ Soranzo N, Rivadeneira F, Chinappen-Horsley U, Malkina I, Richards JB, Hammond N, et al. (April 2009). "Meta-analysis of genome-wide scans for human adult stature identifies novel Loci and associations with measures of skeletal frame size". PLOS Genetics. 5 (4): e1000445. doi:10.1371/journal.pgen.1000445. PMC   2661236 . PMID   19343178.
  20. ↑ Hancock DB, Eijgelsheim M, Wilk JB, Gharib SA, Loehr LR, Marciante KD, et al. (January 2010). "Meta-analyses of genome-wide association studies identify multiple loci associated with pulmonary function". Nature Genetics. 42 (1): 45–52. doi:10.1038/ng.500. PMC   2832852 . PMID   20010835.
  21. 1 2 Kou I, Takahashi Y, Johnson TA, Takahashi A, Guo L, Dai J, et al. (June 2013). "Genetic variants in GPR126 are associated with adolescent idiopathic scoliosis". Nature Genetics. 45 (6): 676–9. doi:10.1038/ng.2639. PMID   23666238. S2CID   205347099.
  22. ↑ Pogoda HM, Sternheim N, Lyons DA, Diamond B, Hawkins TA, Woods IG, et al. (October 2006). "A genetic screen identifies genes essential for development of myelinated axons in zebrafish". Developmental Biology. 298 (1): 118–31. doi: 10.1016/j.ydbio.2006.06.021 . PMID   16875686.
  23. ↑ Monk KR, Naylor SG, Glenn TD, Mercurio S, Perlin JR, Dominguez C, Moens CB, Talbot WS (September 2009). "A G protein-coupled receptor is essential for Schwann cells to initiate myelination". Science. 325 (5946): 1402–5. Bibcode:2009Sci...325.1402M. doi:10.1126/science.1173474. PMC   2856697 . PMID   19745155.
  24. ↑ Waller-Evans H, Prömel S, Langenhan T, Dixon J, Zahn D, Colledge WH, Doran J, Carlton MB, Davies B, Aparicio SA, Grosse J, Russ AP (November 2010). "The orphan adhesion-GPCR GPR126 is required for embryonic development in the mouse". PLOS ONE. 5 (11): e14047. Bibcode:2010PLoSO...514047W. doi: 10.1371/journal.pone.0014047 . PMC   2987804 . PMID   21124978.
  25. ↑ Patra C, van Amerongen MJ, Ghosh S, Ricciardi F, Sajjad A, Novoyatleva T, Mogha A, Monk KR, Mühlfeld C, Engel FB (October 2013). "Organ-specific function of adhesion G protein-coupled receptor GPR126 is domain-dependent". Proceedings of the National Academy of Sciences of the United States of America. 110 (42): 16898–903. Bibcode:2013PNAS..11016898P. doi: 10.1073/pnas.1304837110 . PMC   3801000 . PMID   24082093.
  26. ↑ Geng FS, Abbas L, Baxendale S, Holdsworth CJ, Swanson AG, Slanchev K, Hammerschmidt M, Topczewski J, Whitfield TT (November 2013). "Semicircular canal morphogenesis in the zebrafish inner ear requires the function of gpr126 (lauscher), an adhesion class G protein-coupled receptor gene". Development. 140 (21): 4362–74. doi:10.1242/dev.098061. PMC   4007713 . PMID   24067352.
  27. ↑ Karner CM, Long F, Solnica-Krezel L, Monk KR, Gray RS (August 2015). "Gpr126/Adgrg6 deletion in cartilage models idiopathic scoliosis and pectus excavatum in mice". Human Molecular Genetics. 24 (15): 4365–73. doi:10.1093/hmg/ddv170. PMC   4492399 . PMID   25954032.
  28. ↑ Ravenscroft G, Nolent F, Rajagopalan S, Meireles AM, Paavola KJ, Gaillard D, et al. (June 2015). "Mutations of GPR126 are responsible for severe arthrogryposis multiplex congenita". American Journal of Human Genetics. 96 (6): 955–61. doi:10.1016/j.ajhg.2015.04.014. PMC   4457946 . PMID   26004201.
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