| || 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).
| 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.|
| 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.|
| 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.|
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| 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.|
| 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.|
| Trophinin in cell adhesion and signal transduction.|
| Fukuda MN, Sugihara K.|
| Front Biosci (Elite Ed). 2012 Jan 1;4:342-50. (REVIEW)|
| 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.|
| 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.|
| 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.|
| 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.|
| 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.|
| 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.|
| 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.|
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| 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.|
| 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.|
| 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.|
| 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.|
| 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.|
| 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.|