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MICHIKO N. FUKUDA, PH.D.
Professor
Tumor Microenvironment
858.646.3143 (phone)
858.646.3193 (fax)
michiko@burnham.org
RESEARCH FOCUS, BIOGRAPHY, PUBLICATIONS
Research FocusRole of N-glycan in vivo.
Mammalian cells contain a variety of glycoproteins of which the role of “glyco” part is not yet fully understood. Recent findings of human genetic disease and mutant mouse, in which a gene encoding glycosylation enzyme is inactivated, unveil essential role of these carbohydrate for mammals. Our studies focused on one of such enzyme, α-mannosidase IIx (MX), involved in the biosynthesis of N-glycans, the major form of carbohydrates linked to proteins.
When MX gene was knocked out in the mouse, male mouse became infertile due to an inefficient spermatogenesis. Our study identified a specific N-glycan structure required for the interaction between germ cells and Sertoli cells in the mouse testis (1).
MX functions as the alternative pathway enzyme for MII. Mutant mice lacking both MII/MX die shortly after birth due to respiratory failure (2).
Carbohydrate-mediated cancer metastasis.
Malignant transformation of epithelial cells of internal organs is associated with remarkable qualitative and structural changes in cell surface carbohydrates. Since sialyl Lewis X (sLex), one of cancer-associated carbohydrate antigens, interacts with E-selectin expressed on the surface of blood vessels, interaction between sLex on cancer and E-selectin in the vasculature initiates blood-born metastasis.
We previously established a selectin-ligand mimicry peptide for testing sLex-dependent hematogenous metastasis to the lung (3). However, when sLex-expressing cells were injected intravenously into E-selectin-deficient mutant mice, these cancer cells metastasized to the lung in a similar efficiency as in wild-type mice, suggesting that sLex-dependent cancer metastasis is independent of E-selectin (4). We hypothesize the existence new carbohydrate-binding receptor for carbohydrate-dependent hematogenous cancer metastasis.
Role of trophinin in human embryo implantation and cancer.
Invasion of the trophoblast into the endometrium, an essential element of embryo implantation, resembles invasion of malignant tumors. At the initial phase of implantation, the trophoblast and the uterine epithelium establish their first contact via their respective apical cell membranes. We have identified new molecules, trophinin, tastin, and bystin that mediate cell adhesion between trophoblastic cells and endometrial epithelial cells at the respective apical cell membranes. Trophinin is an intrinsic membrane protein, and tastin and bystin are cytoplasmic proteins. All of these molecules are strongly expressed in cells involved in embryo implantation in humans.
It is known that process of embryo implantation vary significantly among mammalian species. Human embryo implantation is unique as an ectopic pregnancy or ectopic implantation only occurs in humans. Our study revealed that trophinin is expressed during ectopic implantation, which is induced by chorionic gonadotrophin (hCG) secreted from the implanting embryo. Since hCG-beta gene is widely deviated in higher primates, involvement of hCG forms a basis for the unique role of trophinin in human embryo implantation (5).
HCG has been used for pregnancy test in women. In men, hCG serves as a good marker for testicular cancer. We found that testicular cancer patients with high hCG contain trophinin in their tumor and their prognosis are poor. Our study showed that trophinin promotes testicular cancer invasion and metastasis (6). We also found that trophinin is expressed in colon cancer, also in response to hCG (7). Thus, our study provides a logical support for hCG testing in certain human cancers.
When trophectoderm cells (outer layer cells) of human embryo adhere to maternal endometrial epithelial cells, trophectoderm cells are activated and invade maternal tissue. By contrast, trophectoderm cells at non-adherent sites remain silent. We found that trophinin arrests EGF (epidermal growth factor) receptor, and that trophinin-mediated adhesion release EGF receptor from this arrest. Therefore trophinin functions as molecular switch for trophectoderm cells activation (8, 9).
Mechanism of the activation of trophectoderm cells (the outer layer of blastocyst stage of human embryo) by trophinin-mediated cell adhesion. Trophinin and bystin bound together in a cytoplasmic complex, which further interacted with ErbB4 and suppressed its tyrosine kinase activity (left). HB-EGF binds to ErbB4 but protein kinase activity is suppressed by trophinin/bystin (center). Trophinin-mediated cell adhesion is mimicked by binding of GWRQ peptide to trophinin on the cell surface, resulting in dissociation of trophinin from bystin and activation of ErbB4 (right).
Biography
Michiko N. Fukuda earned her Ph.D. in biochemistry at the University of Tokyo in 1980. She did postdoctoral work at Fred Hutchinson Cancer Research Center in Seattle prior to her recruitment to the Burnham Institute for Medical Research in 1982.
Selected Publications
Aoki, R., Suzuki, N., Paria, B. C., Sugihara, K., Akama, T. O., Raab, G., Miyoshi, M., Nadano, D., and Fukuda, M. N. The Bysl gene product, bystin, is essential for survival of mouse embryos. FEBS Lett, 580: 6062-6068, 2006.
Sugihara, K., Sugiyama, D., Byrne, J., Wolf, D. P., Lowitz, K. W., Kobayashi, K., Kabir-Salmani, M., Nadano, D., Aoki, D., Nozawa, S., Nakayama, J., Mustelin, T., Ruoslahti, E., Yamaguchi, N., and Fukuda, M. N. Trophoblastic cell activation by trophinin ligation is implicated in human embryo implantation. Proc. Natl. Acad. Sci. USA. 104: 3799-3804, 2007. (This is featured by Editor's Choice in Science. [DOI: 10.1126/stke.3772007tw85].)
Fukuda, M. N. and Sugihara, K. Signal Transduction in Human Embryo Implantation. Cell Cycle, 6: 1153-1156, 2007.
Sugihara, K., Kabir-Salmani, M., Byrne, J., Wolf , D. P., Lessey, B., Iwashita, M., Aoki, D., Nakayama, J., Fukuda, M. N. Induction of trophinin in human endometrial surface epithelia by CGb and IL-1b. FEBS Letters, 582: 197-202, 2008.
Hatakeyama, S., Sugihara, K., Lee, S.H., Nadano, D., Nakayama, J., Ohyama, C., and Fukuda, M.N. 2008. Enhancement of human sperm motility by trophinin binding peptide. J Urol 180:767-771. (This is featured in editorial comment in the same issue of Journal Urology.)
Fukuda, M. N., Sugihara, K., and Nakayama, J. Trophinin: what embryo implantation teaches us about human cancer. Cancer Biol Ther, 7: 1165, 2008.
Hatakeyama, K., Sugihara, K., Nakayama, J., Akama, T. O., Won, S-M, A., Kawashima, H., Zhang, J., Smith, D. F., Ohyama, C., Fukuda, M., and Fukuda, M. N. Identification of mRNA splicing factors as the endothelial receptor for carbohydrate-dependent lung colonization of cancer cells. Proc. Natl. Acad. Sci. USA, 106: 3095-3100, 2009.
List of Publications via PubMed
(NIH National Library of Medicine)
RESEARCH REPORT
TROPHININ, TASTIN, AND BYSTIN: MOLECULES INVOLVED IN EMBRYO IMPLANTATION
(Download report as PDF)Trophinin is expressed on the surface of the trophectoderm of the blastocyst and endometrial epithelium at the time of implantation. In human placentas, trophinin is internalized from the surface into the lysosomes around 6 weeks of pregnancy and disappears from the placenta after 10 weeks of pregnancy. (See also, Suzuki et al., Proc. Natl. Acad. Sci. U. S. A. 95:5027-5032, 1999.)
