FGFR1OP2

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Fibroblast growth factor receptor oncogene partner 2 (FGFR1OP2) was identified in a study on myeloproliferative syndrome (EMS). The study aimed to identify the partner genes to the fibroblast growth factor receptor 1 (FGFR1) involved in the syndrome. Using the 5'-RACE PCR technique, FGFR1OP2 was identified as a novel gene with no known function.[1]

Function

FGFR1OP2, when fused with the fibroblast growth factor receptor 1 (FGFR1), is shown to cause myeloproliferative syndrome.[1] The protein encoded by the FGFR1 gene belongs to the fibroblast growth factor receptor family.[2] FGFRs usually contain an extracellular ligand binding domain, a single transmembrane domain, and an intracellular tyrosine kinase domain. The extracellular domain specifies which ligand the receptor will bind to and mediates ligand-induced receptor dimerization.[3] When FGFR1OP2 is fused to FGFR1, it may exhibit constitutive kinase activity.[4] Furthermore, FGFR1OP2 is possibly involved in some steps of the wound healing pathway.[5]

Evolutionary Biology

The following tables compare the Homo sapiens FGFR1OP2 gene and protein to orthologs. In both of the following tables, the divergence from the Homo sapiens FGFR1OP2 gene or protein to the ortholog was found using TimeTree.[6] Ortholog mRNA and protein sequences were found using NCBI's BLAST [7] and UCSC's BLAT Tool.[8] The accession numbers, as well as the sequence length and the sequence similarity were compiled using BLAST.[7]

mRNA orthologs to Homo sapiens FGFR1OP2 mRNA
Genus species Common name Divergence (MYA) Accession number Sequence length (base pairs) Sequence similarity
Homo sapiens Human 0 NP_056448.1 3030 100%
Nomascus leucogenys Gibbon 20.4 XM_003265627.1 3020 96%
Bos taurus Cow 94.2 BC148973.1 2616 94%
Canis lupus familiaris Dog 94.2 NM_001197313.1 694 94%
Loxodonta africana Elephant 98.7 XM_003405700.1 762 93%
Sciurus vulgaris Squirrel 92.3 NA 1859 92%
Mus musculus Mouse 92.3 NM_026218.2 2828 89%
Rattus norvegicus Rat 92.3 NM_201421.1 2860 88%
Monodelphis domestica Opossum 162.6 XM_001362357.1 765 88%
Taeniopygia guttata Zebra finch 296 XM_002194575.2 1071 85%
Gallus gallus Chicken 296 NM_001007855.1 3142 83%
Meleagris gallopavo Turkey 296 XM_003202514.1 1275 82%
Anolis carolinensis Anole 296 XM_003221530.1 1964 82%
Trichechus inunguis Manatee 98.7 NA 2752 81%
Oreochromis niloticus Tilapia 400.1 XM_003455706.1 937 79%
Xenopus laevis Frog 371.2 NM_001085932.1 1279 79%
Danio rerio Zebrafish 400.1 NM_199955 1501 78%

The mRNA orthologs sequence similarity to Homo sapiens FGFR1OP2 was graphed as a function of time in order to show how the FGFR1OP2 gene has changed over time. The graph is depicted on the right.

File:MRNAseqID vs divergence.jpg
This graph shows the FGFR1OP2 mRNA sequence identity (% to human) vs. the time since the species diverged (in millions of years) from humans for the mRNA orthologs.

The table below shows the protein orthologs to the Homo sapiens FGFR1OP2 protein. FGFR1OP2 is conserved in all clades of the animal kingdom, as seen in the table below.

Protein orthologs to Homo sapiens FGFR1OP2
Genus species Common name Divergence (MYA) Accession number Sequence length (amino acids) Sequence similarity
Homo sapiens Human 0 NP_056448.1 253 100%
Saimiri boliviensis boliviensis Squirrel monkey 42.6 XP_003926645.1 253 99%
Loxodonta africana Elephant 98.7 XP_003405748.1 253 99%
Mus musculus Mouse 92.3 NP_080494.1 253 99%
Monodelphis domestica Opossum 162.6 XP_001362394.1 254 96%
Meleagris gallopavo Turkey 296 XP_003202562.1 215 83%
Anolis carolinensis Anole 296 XP_003221578.1 214 82%
Oreochromis niloticus Tilapia 400.1 XP_003455754.1 224 78%
Xenopus laevis Frog 371.2 NP_001079401.1 215 77%
Danio rerio Zebrafish 400.1 NP_956249.1 215 77%
Strongylocentrotus purpuratus Sea urchin 742.9 XP_786805.2 250 66%
Crassostrea gigas Oyster 782.7 EKC25301.1 233 64%
Capitella teleta Annelid 782.7 ELU02494.1 287 63%
Nematostella vectensis Sea anemone 855.3 XP_001639733.1 174 62%
Ciona intestinalis Sea squirt 722.5 XP_002130340.1 236 61%
Tribolium castaneum Beetle 782.7 XP_974301.1 201 57%
Loa loa Nematode 937.5 EFO20048.2 266 51%
Schistosoma mansoni Blood fluke 792.4 CCD58880.1 342 51%
Amphimedon queenslandica Sponge 716.5 XP_003387498.1 221 48%

Gene

File:FGFR1OP2 gene neighborhood.png
ASUN is located downstream and TM7SF3 is located slightly upstream from the FGFR1OP2 gene locus.

There are three transcript variants for the FGFR1OP2 gene, with the first being the longest.[9] FGFR1OP2 is also known as HSPC123-like protein (HSPC123L) and wound inducible transcript 3.0 (wit3.0).[9]

File:FGFR1OP2 promoter.png
The promoter region of the Homo sapiens FGFR1OP2 gene shown with likely binding sites for transcription factors. ElDorado was used to analyze the promoter of FGFR1OP2, and the most likely binding transcription factors are shown.[10]

Locus

The Homo sapiens FGFR1OP2 gene is located on chromosome 12, with its specific locus being 12p11.23.[9] The Homo sapiens asunder spermatogenesis regulator (ASUN) gene (NCBI Reference Sequence NM_018164.2) is located directly upstream from FGFR1OP2.[11] The ASUN gene is a regulator of development and the mitotic cell cycle.[12] The Homo sapiens transmembrane 7 superfamily member 3 (TM7SF3) gene is located slightly downstream from FGFR1OP2.[13]

Promoter

Transcription factors that bind to the FGFR1OP2 promoter
Transcription factor (T.F.) Full name Function Matrix similarity Strand T.F. binds Sequence T.F. binds
AP1 Activator protein 1 Differentiation, proliferation, apoptosis 0.874 + gggaGAGTcagcg
Smad3 Mothers against decapentaplegic homolog 3 TGF-beta signaling factor 0.983 + agtGTCTggtg
DRE Dioxin response element Bound by AHR/AHRNT heterodimer 0.971 + gcgcgcgtgcGCGTgcacacacaca
HAS HIF-1 ancillary sequence Induce vascular endothelial growth 0.923 + acaCACGcact
RBP2 Retinoblastoma-binding protein 2 Demethylase 1.000 + GCACagcgc
PLAG1 Pleomorphic adenoma gene 1 Cell proliferation 1.000 - gaGGGGgaagggaggcttggccg
KLF7 Kruppel-like factor 7 Regulate cell proliferation, differentiation, and survival 0.972 + ggaagagGGCGgggcca
NFAT Nuclear factor of activated T-cells Immune response 0.994 + aaggaGGAAaaaaaaagcc
NFAT Nuclear factor of activated T-cells Immune response 0.955 - cgggtGGAAaatctcgagg
Ikaros2 Ikaros zinc finger Potential regulator of lymphocytes 0.986 + cattGGGAagcag
Ikaros2 Ikaros zinc finger Potential regulator of lymphocytes 0.980 - gactGGGAaaatt
PLAG1 Pleomorphic adenoma gene 1 Cell proliferation 1.000 - taGGGGgccgtggttggtacttc
WT Wilms tumor suppressor EGR/nerve growth factor 0.948 - gaccgggTGGGtgggtc
AREB6 Atp1a1 regulatory element binding factor 6 Negative regulator of IL-2 0.982 + ggccgGTTTcccc
NMP4 Nuclear matrix protein 4 Cas-interacting zinc finger protein 0.994 + ggAAAAactcg
SPI1 SPI-1 proto-oncogene Hematopoietic transcription factor 0.918 + ggaagggaGGAAtagg
KLF7 Kruppel-like factor 7 Regulate cell proliferation, differentiation, and survival 0.962 - aaggcagGGCGgggccc
NFAT Nuclear factor of activated T-cells Immune response 0.989 + cgcgaGGAAagaaatctcg
TBX20 Brachyury gene Mesoderm developmental factor 1.000 + ggtcggcggAGGTgtctaccccg
STAT3 Signal transducer and activator of transcription 3 Activate transcription 0.940 + tggcTTCCcggccttccgt

Protein

File:FGFR1OP2 sequence analysis for structure.png
The protein sequence of FGFR1OP2 was analyzed using PELE, and appears to be made up of mostly alpha helices.
File:Mus musculus FGFR1OP2 protein structure from ModBase.png
Mus musculus FGFR1OP2 protein structure from ModBase

There are three isoforms of the FGFR1OP2 protein. Transcript variant 1 consists of 253 amino acids and weighs 29.4 kilodaltons.[9] FGFR1OP2's isoelectric point is 5.61.[14] The FGFR1OP2 protein does not have a signal sequences, and therefore is not secreted.[15]

Domains

FGFR1OP2 has a domain of unknown function, designated DUF837.[9]

Protein Structure

Using the PELE program of Biology WorkBench the protein sequence of FGFR1OP2 was analyzed, and FGFR1OP2 appears to be completely composed of alpha helices.[14] No structural models for the Homo sapiens FGFR1OP2 protein could be found, but the Mus musculus FGFR1OP2 protein's structure can be seen below.


Expression

The expression of FGFR1OP2 was analyzed via the Gene Expression Omnibus at NCBI.[16] The following are findings from the Gene Expression Onmibus database:

  • There is a slightly elevated expression level of FGFR1OP2 in pulmonary sarcoidosis, suggesting FGFR1OP2 operates in part of the wound healing pathway.
  • FGFR1OP2 is strongly upregulated when compared to the control in an increased immune response triggered by the VAF347 ligand. FGFR1OP2 is upregulated in the monocyte derived dendritic cell response to the VAF347 ligand. VAF347 activates the aryl hydrocarbon receptor and acts on monocytes and naive CD4+ Th cells to promote development of IL-22 secreting Th cells.[17]
  • Langerhans cells show decreased expression of FGFR1OP2 with the null aryl hydrocarbon receptor (ligand is VAF347) in Mus musculus.
  • The gene is also highly expressed compared to control samples in monocytopenia.
  • It is expressed in cases of leukemia; it may have a linkage to the disease.
  • FGFR1OP2 shows low expression levels in septic splenocytes in Mus musculus.
  • FGFR1OP2 is expressed in fetal reticulocytes but not adult reticulocytes, suggesting it may play a role in the development of red blood cells.

Interactions

File:FGFR1OP2 interacting proteins.png
FGFR1OP2 interacting proteins[18]

Using the STRING database and Gene Cards, proteins that possibly interact with FGFR1OP2 were identified, and they are shown in the table below.[5][18]

FGFR1OP2 Interacting Proteins
Interactant Full name Function Source(s)
STK24 Serine/threonine kinase 24 Protein kinase Gene Cards
TRAF3IP3 TRAF3 interacting protein Adapter molecule Gene Cards, STRING
ZRANB1 Zinc finger, RAN-binding domain containing 1 Positive regulator of Wnt signaling, cytoskeletal organization Gene Cards
PPP2R1A Protein phosphatase 2 Negative control of cell growth and division Gene Cards
STRN Striatin, calmodulin binding protein Scaffold protein Gene Cards, STRING
FAM40A Family with sequence similarity 40, member A Cytoskeletal organization STRING
PDCD10 Programmed cell death 10 Regulate apoptotic pathways STRING
MST4 Serine/threonine kinase 3 Mediator of cell growth STRING
SIKE1 Suppressor of IKBKE1 Suppressor of IKK-epsilon and TBK1 inhibitor STRING
MOBKL3 Mps one binder kinase activator-like 3 Spindle pole body duplication and mitotic checkpoint regulation STRING

Clinical Significance

Single-nucleotide polymorphisms (SNPs) in the FGFR1OP2 gene were found to lead to edentulism in the mandible of a small Korean population (134 subjects aged 60–80 years).[19] Also, when FGFR1OP2 is fused to FGFR1, 8p11 myeloproliferative syndrome can result.[1]

References

  1. ↑ 1.0 1.1 1.2 Grand, E. K. (2006). "Identification of a novel gene, fgfr1op2, fused to fgfr1 in 8p11 myeloproliferative syndrome". Genes, Chromosomes & Cancer. 40 (1): 78. doi:10.1002/gcc.20023.
  2. ↑ Ornitz, DM; Xu (1996). "Receptor specificity of the fibroblast growth factor family". Journal of Biological Chemistry. 271 (25): 15292–15297. doi:10.1074/jbc.271.25.15292. PMID 8663044.
  3. ↑ J. Schlessinger, A. Ullrich (September 1992). "Growth factor signaling by receptor tyrosine kinases". Neuron. 9 (3): 383–391. doi:10.1016/0896-6273(92)90177-f.
  4. ↑ "FGFR1OP2". PhosphoSitePlus®. Retrieved 2013-01-27.
  5. ↑ 5.0 5.1 "FGFR1OP2". GeneCards. Retrieved 2013-01-27.
  6. ↑ Hedges SB, Dudley J & Kumar S. "TimeTree: a public knowledge-base of divergence times among organisms". Retrieved 12 February 2013.
  7. ↑ 7.0 7.1 "BLAST (Basic Local Alignment Search Tool)". NCBI. Retrieved 3 May 2013.
  8. ↑ Kent, Jim. "BLAT". UCSC Genome Bioinformatics. Retrieved 27 March 2013.
  9. ↑ 9.0 9.1 9.2 9.3 9.4 "Homo sapiens FGFR1 oncogene partner 2 (FGFR1OP2), transcript variant 1, mRNA".
  10. ↑ "ElDorado". Genomatix. Retrieved 2 March 2013.
  11. ↑ "Human Genome Browser". Genome Bioinformatics Group of UC Santa Cruz.
  12. ↑ "Homo sapiens asunder spermatogenesis regulator (ASUN), mRNA". NCBI.
  13. ↑ "Homo sapiens transmembrane 7 superfamily member 3 (TM7SF3), mRNA". NCBI.
  14. ↑ 14.0 14.1 "SDSC Biology WorkBench". San Diego Supercomputer Center.
  15. ↑ Petersen, Thomas Nordahl; Søren Brunak; Gunnar von Heijne; Henrik Nielsen (2011). "SignalP 4.0: discriminating signal peptides from transmembrane regions". Nature Methods. 8 (10): 785–786. doi:10.1038/nmeth.1701. PMID 21959131.
  16. ↑ 16.0 16.1 Edgar, R; Domrachev M; Lash AE (Jan 2002). "Gene Expression Omnibus: NCBI gene expression and hybridization array data repository". Nucleic Acids Res. 30 (1): 207–10. doi:10.1093/nar/30.1.207.
  17. ↑ Baba, N (2012). "The aryl hydrocarbon receptor (ahr) ligand vaf347 selectively acts on monocytes and naïve cd4+ th cells to promote the development of il-22-secreting th cells". Human Immunology. 73 (8): 795–800. doi:10.1016/j.humimm.2012.05.002.
  18. ↑ 18.0 18.1 "STRING Database".
  19. ↑ Kim; et al. (2012). "Association between fgfr1op2/wit3.0 polymorphisms and residual ridge resorption of mandible in korean population". PLoS ONE. 7 (8): e42734. doi:10.1371/journal.pone.0042734. PMC 3412816. PMID 22880093.

External links

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