Atlas of Genetics and Cytogenetics in Oncology and Haematology


Home   Genes   Leukemias   Solid Tumors   Cancer-Prone   Deep Insight   Case Reports   Journals  Portal   Teaching   

X Y 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 NA

TRO (trophinin)

Written2013-08Michiko N Fukuda, Kazuhiro Sugihara
Sanford-Burnham Medical Research Institute, La Jolla, California, USA (MNF); Hamamatsu University School of Medicine, Shizuoka, Japan (KS)

(Note : for Links provided by Atlas : click)

Identity

Alias_symbol (synonym)MAGE-D3
KIAA1114
MAGED3
Other aliasMAGE-d3
HGNC (Hugo) TRO
LocusID (NCBI) 7216
Atlas_Id 47688
Location Xp11.21  [Link to chromosome band Xp11]
Location_base_pair Starts at 54920563 and ends at 54931431 bp from pter ( according to hg19-Feb_2009)  [Mapping TRO.png]
 
  Figure 1. Genomic organization of TRO.
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
FAM126A (7p15.3) / TRO (Xp11.21)RNU12 (22q13.2) / TRO (Xp11.21)

DNA/RNA

 
  Figure 2. TRO gene structure, trophinin/magphinin transcripts and proteins. Diagram shows exon, introns of the human TRO. Predicted alternatively spliced mRNAs and polypeptides of human magphini and trophinin are based on the EST database and previous study of mouse Tro (Aoyama et al., 2008; Saburi et al., 2001). Exons are shown by shaded boxes, open reading frames (ORFs) are shown by solid boxes, and untranslated regions (UTRs) are represented by open boxes. Human magphinin proteins do not share peptide sequence with trophinin protein (blue). The predicted molecular sizes of human trophinin, magphinin-α, -β, and -γ are 69,4, 74,9, 77,0 and 33,5 kDa, respectively.
Description TRO locates on X chromosome Xp11.21-22 (Pack et al., 1997). It contains 14 exons spanning 10,8 kb of genomic DNA (Aoyama et al., 2005).
Transcription Although TRO produces a transcript with an open reading frame encoding a 138-kDa protein, previous studies did not detect this protein in vivo and in vitro (Nadano et al., 2002). Instead, TRO produces two distinct proteins, magphinin (MAGE D3) and trophinin (Aoyama et al., 2008; Aoyama et al., 2005; Saburi et al., 2001). Translation for magphinin starts at AUG codon in exon 2, whereas translation for TRO starts at AUG codon in exon 12. Entire trophinin protein is encoded by exon 12. There are no sequence overlaps between magphinin and trophinin proteins (figure 2).
Pseudogene None.

Protein

 
  Figure 3. Structure of human trophinin protein. Left: peptide sequence of human trophinin. Cytoplasmic domain (blue) including N-terminus is followed by decapeptide repeats (black), which conform transmembrane domain and extracellular domain including C-terminus. Decapeptide repeats are thought to provide basis for cell adhesion machinery by hemophilic trophinin-trophinin binding. Right: proposed topology of trophinin protein, with decapeptide repeats as outer cellular and N-terminal region in the cytoplasm.
Description Human trophinin is a 69 kDa protein composed of 749 amino acid residues. Trophinin protein contains many decapeptide repeats (figure 3). Although trophinin is not a typical membrane protein and does not contain clear membrane spanning domain, experimental data indicated that trophinin is transmembrane protein. N-terminal region of trophinin is in the cytoplasm, and other region composed of decapeptide repeats is extracellular. Trophinin was identified by functional cloning as the molecule potentially mediating the initial adhesion of the human embryo to the uterine epithelia between trophoblastic and endometrial cells (Fukuda et al., 1995; Nakayama et al., 2003; Sugihara et al., 2007; Suzuki et al., 1998; Tamura et al., 2011). Trophinin associates with two cytoplasmic proteins bystin and tastin, of which complex functions as cell adhesion machinery through trophinin-trophinin binding between trophinin-expressing cells. Trophinin, bystin and tastin also function as molecular switch in signal transduction. Thus in trophoblastic cells trophinin-medited cell adhesion promotes cell growth and invasion (Sugihara et al., 2007), whereas in endometrial epithelial cells trophinin-mediated cell adhesion triggers apoptosis to accept invading embryo (Tamura et al., 2011).
Expression TRO expressed strongly in trophectoderm cells and endometrial epithelial cells during embryo implantation (Fukuda et al., 1995; Nakayama et al., 2003; Suzuki et al., 1999). In early pregnancy human placenta (6 weeks), TRO transcripts and protein were found in syncytiotrophoblast in the chorionic villi, and in endometrial decidual cells at the utero placental interface. Trophinin disappears from placenta in later stage of pregnancy (more than 10 weeks), trophinin disappears from human placenta (Suzuki et al., 1999).
In the pregnant mouse uterus, trophinin transcripts are expressed during the time coinciding with those of blastocyst implantation (Suzuki et al., 2000).
In addition, TRO is strongly expressed in post mitotic neurons. In adult rat brain, trophinin is expressed in the subventricular zone, one of the region where active neurogenesis occurs (Ma et al., 2006).
Trophinin is expressed in brain and mature sperm in testis. Low levels TRO expression is detected in a variety of tissues, including liver, kidney, stomach, muscle and skin.
Trophinin is expressed in testicular cancer (Hatakeyama et al., 2004), colon cancer (Harada et al., 2007), lung cancer (Chen et al., 2007).
Localisation Trophinin protein was found in the pinopodes, unique structure found in endometrial epithelial cells at embryo implantation site, which was mimicked by primary culture of human endometrial epithelial cells in medium containing human chorionic gonadotropin (hCG) (Sugihara et al., 2008). In cultured cells, trophinin was found in the nuclear membranes and cytoplasm (Aoyama et al., 2005).
In both human and mouse, trophinin protein was found in the tail of matured sperm cells.
 
  Figure 4. Molecular switch by trophinin in trophectoderm cells of human embryo implantation. Monkey blastocyst cultured in vitro was activated by GWRQ peptide, that mimics trophinin-mediated cell adhesion through the mechanism of ErbB4 receptor tyrosine kinase (Sugihara et al., 2007).
Function Trophinin function in human embryo implantation: Trophinin expressed on an apical cell membranes of trophectoderm cells of blastocyst and endometrial epithelial cells mediates cell adhesion between these two cell types through hemophilic trophinin-trophinin binding (Fukuda et al., 1995). The signal of trophinin-mediated cell adhesion is transmitted to the cytoplasm, leading into trophectoderm cell activation for proliferation and invasion (Fukuda and Sugihara, 2007; Fukuda and Sugihara, 2008; Fukuda and Sugihara, 2012; Sugihara et al., 2007). Thus trophinin functions as a molecular switch in signal transduction. The mechanism underlying this trophinin-ligation triggered cell activation involves receptor tyrosine kinase ErbB4 and bystin as shown in figure 4. In endometrial epithelial cells, trophinin-mediated cell adhesion triggered signal transduction through PKC-γ, leading into apoptosis to accept invading embryo (Tamura et al., 2011).
In ectopic tubal pregnancies, high levels of trophinin was found in both trophoblasts and tubal epithelia. Trophinin expression in maternal cells was particularly high in the area adjacent to the trophoblasts, whereas trophinin was barely detectable in intact fallopian tubes from women with in utero pregnancies or without pregnancies. The human chorionic gonadotrophin (hCG), trophinin expression was enhanced in epithelial cells. As both beta-subunit of hCG and trophinin genes have diverged in mammals, the study suggests a unique role of hCG and trophinin in human embryo implantation (Nakayama et al., 2003).
Tro gene knock-out mouse did not show infertility (Nadano et al., 2002). This evidence in mouse, and induction of TRO expression by hCG (Nakayama et al., 2003; Sugihara et al., 2008), and significant genetic diversion CGβ between non-human primate and human (Maston and Ruvolo, 2002) suggest that function of trophinin in embryo implantation is unique to humans.
Trophinin function in sperm motility: Trophinin suppresses sperm tail motility in human and mouse, which can be activated by trophinin-binding peptide (Hatakeyama et al., 2008; Park et al., 2012).
Trophinin function in neuronal cells: In adult rat brain, trophinin is expressed in the subventricular zone together with bystin, implicated to active neurogenesis in this region (Ma et al., 2006).
Homology None.

Mutations

Note No mutation of TRO in human is known.

Implicated in

Note
  
Entity Various cancers
Note Trophinin is overexpressed in some human cancers including colon cancer (Harada et al., 2007) and testicular cancer (Hatakeyama et al., 2004), which coincides with hCG. In these cancers, trophinin expression correlates to invasiveness. Correlation of trophinin to cancer invasiveness were reported in lung cancer (Chen et al., 2007) and bladder carcinoma cells (Chang et al., 2009). On the other hand, trophinin is negatively correlated to the malignancy in ovarian cancer (Baba et al., 2007; Fukuda et al., 2008).
  

Bibliography

Nuclear localization of magphinins, alternative splicing products of the human trophinin gene.
Aoyama J, Akazawa Y, Kasahara K, Higashiyama Y, Kikuchi I, Fukumoto Y, Saburi S, Nakayama Y, Fukuda MN, Yamaguchi N.
J Cell Biochem. 2008 Feb 15;103(3):765-77.
PMID 17559068
 
Apical cell adhesion molecule, trophinin, localizes to the nuclear envelope.
Aoyama J, Nakayama Y, Sugiyama D, Saburi S, Nadano D, Fukuda MN, Yamaguchi N.
FEBS Lett. 2005 Nov 21;579(28):6326-32. Epub 2005 Oct 19.
PMID 16288751
 
Trophinin is a potent prognostic marker of ovarian cancer involved in platinum sensitivity.
Baba T, Mori S, Matsumura N, Kariya M, Murphy SK, Kondoh E, Kusakari T, Kuroda H, Mandai M, Higuchi T, Takakura K, Fukuda MN, Fujii S.
Biochem Biophys Res Commun. 2007 Aug 24;360(2):363-9. Epub 2007 Jun 19.
PMID 17597582
 
Enhanced expression of trophinin promotes invasive and metastatic potential of human gallbladder cancer cells.
Chang XZ, Yu J, Zhang XH, Yin J, Wang T, Cao XC.
J Cancer Res Clin Oncol. 2009 Apr;135(4):581-90. doi: 10.1007/s00432-008-0492-1. Epub 2008 Oct 10.
PMID 18846386
 
Identification of trophinin as an enhancer for cell invasion and a prognostic factor for early stage lung cancer.
Chen KY, Lee YC, Lai JM, Chang YL, Lee YC, Yu CJ, Huang CY, Yang PC.
Eur J Cancer. 2007 Mar;43(4):782-90. Epub 2007 Jan 24.
PMID 17254769
 
Trophinin in cell adhesion and signal transduction.
Fukuda MN, Sugihara K.
Front Biosci (Elite Ed). 2012 Jan 1;4:342-50. (REVIEW)
PMID 22201876
 
The role of trophinin, an adhesion molecule unique to human trophoblasts, in progression of colorectal cancer.
Harada O, Suga T, Suzuki T, Nakamoto K, Kobayashi M, Nomiyama T, Nadano D, Ohyama C, Fukuda MN, Nakayama J.
Int J Cancer. 2007 Sep 1;121(5):1072-8.
PMID 17487845
 
Enhancement of human sperm motility by trophinin binding peptide.
Hatakeyama S, Sugihara K, Lee SH, Nadano D, Nakayama J, Ohyama C, Fukuda MN.
J Urol. 2008 Aug;180(2):767-71. doi: 10.1016/j.juro.2008.03.185. Epub 2008 Jun 13.
PMID 18554632
 
Expression of trophinin and bystin identifies distinct cell types in the germinal zones of adult rat brain.
Ma L, Yin M, Wu X, Wu C, Yang S, Sheng J, Ni H, Fukuda MN, Zhou J.
Eur J Neurosci. 2006 May;23(9):2265-76.
PMID 16706835
 
Chorionic gonadotropin has a recent origin within primates and an evolutionary history of selection.
Maston GA, Ruvolo M.
Mol Biol Evol. 2002 Mar;19(3):320-35.
PMID 11861891
 
Significant differences between mouse and human trophinins are revealed by their expression patterns and targeted disruption of mouse trophinin gene.
Nadano D, Sugihara K, Paria BC, Saburi S, Copeland NG, Gilbert DJ, Jenkins NA, Nakayama J, Fukuda MN.
Biol Reprod. 2002 Feb;66(2):313-21.
PMID 11804944
 
Implantation-dependent expression of trophinin by maternal fallopian tube epithelia during tubal pregnancies: possible role of human chorionic gonadotrophin on ectopic pregnancy.
Nakayama J, Aoki D, Suga T, Akama TO, Ishizone S, Yamaguchi H, Imakawa K, Nadano D, Fazleabas AT, Katsuyama T, Nozawa S, Fukuda MN.
Am J Pathol. 2003 Dec;163(6):2211-9.
PMID 14633596
 
Assignment of trophoblast/endometrial epithelium cell adhesion molecule trophinin gene TRO to human chromosome bands Xp11.22-->p11.21 by in situ hybridization.
Pack SD, Tanigami A, Ledbetter DH, Sato T, Fukuda MN.
Cytogenet Cell Genet. 1997;79(1-2):123-4.
PMID 9533028
 
Enhancement of mouse sperm motility by trophinin-binding peptide.
Park SK, Yoon J, Wang L, Shibata TK, Motamedchaboki K, Shim KJ, Chang MS, Lee SH, Tamura N, Hatakeyama S, Nadano D, Sugihara K, Fukuda MN.
Reprod Biol Endocrinol. 2012 Nov 29;10:101. doi: 10.1186/1477-7827-10-101.
PMID 23194061
 
The trophinin gene encodes a novel group of MAGE proteins, magphinins, and regulates cell proliferation during gametogenesis in the mouse.
Saburi S, Nadano D, Akama TO, Hirama K, Yamanouchi K, Naito K, Tojo H, Tachi C, Fukuda MN.
J Biol Chem. 2001 Dec 28;276(52):49378-89. Epub 2001 Oct 5.
PMID 11590179
 
Induction of trophinin in human endometrial surface epithelia by CGbeta and IL-1beta.
Sugihara K, Kabir-Salmani M, Byrne J, Wolf DP, Lessey B, Iwashita M, Aoki D, Nakayama J, Fukuda MN.
FEBS Lett. 2008 Jan 23;582(2):197-202. Epub 2007 Dec 17.
PMID 18078818
 
Trophinin expression in the mouse uterus coincides with implantation and is hormonally regulated but not induced by implanting blastocysts.
Suzuki N, Nadano D, Paria BC, Kupriyanov S, Sugihara K, Fukuda MN.
Endocrinology. 2000 Nov;141(11):4247-54.
PMID 11089559
 
A cytoplasmic protein, bystin, interacts with trophinin, tastin, and cytokeratin and may be involved in trophinin-mediated cell adhesion between trophoblast and endometrial epithelial cells.
Suzuki N, Zara J, Sato T, Ong E, Bakhiet N, Oshima RG, Watson KL, Fukuda MN.
Proc Natl Acad Sci U S A. 1998 Apr 28;95(9):5027-32.
PMID 9560222
 
Trophinin-mediated cell adhesion induces apoptosis of human endometrial epithelial cells through PKC-delta.
Tamura N, Sugihara K, Akama TO, Fukuda MN.
Cell Cycle. 2011 Jan 1;10(1):135-43. Epub 2011 Jan 1.
PMID 21191175
 

Citation

This paper should be referenced as such :
Fukuda, MN ; Sugihara, K
TRO (trophinin)
Atlas Genet Cytogenet Oncol Haematol. 2014;18(3):189-193.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/TROID47688chXp11.html


External links

Nomenclature
HGNC (Hugo)TRO   12326
Cards
AtlasTROID47688chXp11
Entrez_Gene (NCBI)TRO  7216  trophinin
AliasesMAGE-d3; MAGED3
GeneCards (Weizmann)TRO
Ensembl hg19 (Hinxton)ENSG00000067445 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000067445 [Gene_View]  chrX:54920563-54931431 [Contig_View]  TRO [Vega]
ICGC DataPortalENSG00000067445
TCGA cBioPortalTRO
AceView (NCBI)TRO
Genatlas (Paris)TRO
WikiGenes7216
SOURCE (Princeton)TRO
Genetics Home Reference (NIH)TRO
Genomic and cartography
GoldenPath hg38 (UCSC)TRO  -     chrX:54920563-54931431 +  Xp11.21   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)TRO  -     Xp11.21   [Description]    (hg19-Feb_2009)
EnsemblTRO - Xp11.21 [CytoView hg19]  TRO - Xp11.21 [CytoView hg38]
Mapping of homologs : NCBITRO [Mapview hg19]  TRO [Mapview hg38]
OMIM300132   
Gene and transcription
Genbank (Entrez)AB029037 AF349719 AF349720 AF349721 AF349722
RefSeq transcript (Entrez)NM_001039705 NM_001271183 NM_001271184 NM_016157 NM_177556 NM_177557
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)TRO
Cluster EST : UnigeneHs.743294 [ NCBI ]
CGAP (NCI)Hs.743294
Alternative Splicing GalleryENSG00000067445
Gene ExpressionTRO [ NCBI-GEO ]   TRO [ EBI - ARRAY_EXPRESS ]   TRO [ SEEK ]   TRO [ MEM ]
Gene Expression Viewer (FireBrowse)TRO [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)7216
GTEX Portal (Tissue expression)TRO
Human Protein AtlasENSG00000067445-TRO [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ12816   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ12816  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ12816
Splice isoforms : SwissVarQ12816
PhosPhoSitePlusQ12816
Domaine pattern : Prosite (Expaxy)MAGE (PS50838)   
Domains : Interpro (EBI)MHD_dom   
Domain families : Pfam (Sanger)MAGE (PF01454)   
Domain families : Pfam (NCBI)pfam01454   
Domain families : Smart (EMBL)MAGE (SM01373)  
Conserved Domain (NCBI)TRO
DMDM Disease mutations7216
Blocks (Seattle)TRO
SuperfamilyQ12816
Human Protein Atlas [tissue]ENSG00000067445-TRO [tissue]
Peptide AtlasQ12816
HPRD02134
IPIIPI00029683   IPI00828043   IPI00791934   IPI00645649   IPI00788795   IPI00789312   IPI00789963   IPI00790643   IPI00747374   IPI00791791   IPI00794140   IPI00794648   IPI00848038   IPI00795770   IPI00927381   IPI00925538   IPI00925313   
Protein Interaction databases
DIP (DOE-UCLA)Q12816
IntAct (EBI)Q12816
FunCoupENSG00000067445
BioGRIDTRO
STRING (EMBL)TRO
ZODIACTRO
Ontologies - Pathways
QuickGOQ12816
Ontology : AmiGOprotein binding  nucleus  cytoplasm  plasma membrane  integral component of plasma membrane  homophilic cell adhesion via plasma membrane adhesion molecules  embryo implantation  negative regulation of cell growth  
Ontology : EGO-EBIprotein binding  nucleus  cytoplasm  plasma membrane  integral component of plasma membrane  homophilic cell adhesion via plasma membrane adhesion molecules  embryo implantation  negative regulation of cell growth  
NDEx NetworkTRO
Atlas of Cancer Signalling NetworkTRO
Wikipedia pathwaysTRO
Orthology - Evolution
OrthoDB7216
GeneTree (enSembl)ENSG00000067445
Phylogenetic Trees/Animal Genes : TreeFamTRO
HOVERGENQ12816
HOGENOMQ12816
Homologs : HomoloGeneTRO
Homology/Alignments : Family Browser (UCSC)TRO
Gene fusions - Rearrangements
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerTRO [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)TRO
dbVarTRO
ClinVarTRO
1000_GenomesTRO 
Exome Variant ServerTRO
ExAC (Exome Aggregation Consortium)ENSG00000067445
GNOMAD BrowserENSG00000067445
Genetic variants : HAPMAP7216
Genomic Variants (DGV)TRO [DGVbeta]
DECIPHERTRO [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisTRO 
Mutations
ICGC Data PortalTRO 
TCGA Data PortalTRO 
Broad Tumor PortalTRO
OASIS PortalTRO [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICTRO  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDTRO
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
LOVD (Leiden Open Variation Database)X-chromosome gene database
BioMutasearch TRO
DgiDB (Drug Gene Interaction Database)TRO
DoCM (Curated mutations)TRO (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)TRO (select a term)
intoGenTRO
NCG5 (London)TRO
Cancer3DTRO(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM300132   
Orphanet
MedgenTRO
Genetic Testing Registry TRO
NextProtQ12816 [Medical]
TSGene7216
GENETestsTRO
Target ValidationTRO
Huge Navigator TRO [HugePedia]
snp3D : Map Gene to Disease7216
BioCentury BCIQTRO
ClinGenTRO
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD7216
Chemical/Pharm GKB GenePA37002
Clinical trialTRO
Miscellaneous
canSAR (ICR)TRO (select the gene name)
Probes
Litterature
PubMed44 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineTRO
EVEXTRO
GoPubMedTRO
iHOPTRO
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

Search in all EBI   NCBI

© Atlas of Genetics and Cytogenetics in Oncology and Haematology
indexed on : Thu Oct 12 16:36:06 CEST 2017

Home   Genes   Leukemias   Solid Tumors   Cancer-Prone   Deep Insight   Case Reports   Journals  Portal   Teaching   

For comments and suggestions or contributions, please contact us

jlhuret@AtlasGeneticsOncology.org.