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PNAS 104 (10): 3799-3804

Copyright © 2007 by the National Academy of Sciences.


Trophoblast cell activation by trophinin ligation is implicated in human embryo implantation

Kazuhiro Sugihara*,{dagger},{ddagger}, Daijiro Sugiyama*,§, James Byrne, Don P. Wolf, Kevin P. Lowitz*, Yoichi Kobayashi*, Maryam Kabir-Salmani{dagger}, Daita Nadano*,||, Daisuke Aoki{ddagger}, Shiro Nozawa{ddagger}, Jun Nakayama**, Tomas Mustelin{dagger}{dagger}, Erkki Ruoslahti{ddagger}{ddagger}, Naoto Yamaguchi§, and Michiko N. Fukuda*,§§

*Cancer Research Center and {dagger}{dagger}Inflammation and Infectious Disease Center, Burnham Institute for Medical Research, 10901 North Torrey Pines Road, La Jolla, CA 92037; {dagger}Department of Gynecology and Obstetrics, Kyorin University School of Medicine, Tokyo 181-8611, Japan; {ddagger}Department of Gynecology and Obstetrics, Keio University School of Medicine, Tokyo 160-8582, Japan; §Department of Molecular Cell Biology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba 260-8675, Japan; Division of Reproductive Sciences, Oregon National Primate Research Center, Beaverton, OR 97006; ||Department of Applied Molecular Biosciences, Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya 464-8601, Japan; **Department of Pathology, Shinshu University School of Medicine, Matsumoto 390-8621, Japan; and {ddagger}{ddagger}Burnham Institute for Medical Research, 1105 Life Sciences Technology Building, University of California, Santa Barbara, CA 93106

Contributed by Erkki Ruoslahti, January 5, 2007

Received for publication September 14, 2006.

Abstract: During human embryo implantation, trophectoderm mediates adhesion of the blastocyst to the uterine epithelium. The rapid growth of the embryo and invasion of the maternal tissue suggest adhesion-induced activation of the embryonal cells. We show here that ligation of trophinin, a homophilic cell adhesion molecule expressed on trophoblastic cells, induces tyrosine phosphorylation in trophinin-expressing trophoblastic HT-H cells. The phosphorylation could be induced in HT-H cells with the binding of trophinin-expressing cells or anti trophinin antibodies. Trophinin-dependent tyrosine phosphorylation was associated with actin reorganization. We also isolated trophinin-binding peptides from phage libraries. These peptides exhibited the consensus sequence GWRQ and seemed to reproduce the effects of trophinin-mediated cell adhesion. Upon binding of a GWRQ peptide, HT-H cells became highly proliferative and motile. HT-H cells expressed ErbB family receptors and bound EGF and heparin-binding EGF-like growth factor (HB-EGF), but ErbB family receptor phosphorylation in these cells required GWRQ. In the absence of GWRQ, trophinin interacted with the cytoplasmic protein bystin, which binds to ErbB4 and blocks its autophosphorylation. In HT-H cells, GWRQ peptide dissociated trophinin from bystin, and ErbB4 was activated. Culturing monkey blastocysts in the presence of the peptide increased total number and motility of the trophectoderm cells. These results suggest that trophinin-mediated cell adhesion functions as a molecular switch for trophectoderm activation in human embryo implantation.

Key Words: BYSL • ErbB4 • pregnancy • receptor tyrosine kinase • stem cells

Freely available online through the PNAS open access option.

Author contributions: K.S., M.K.-S., D.A., S.N., J.N., N.Y., and M.N.F. designed research; K.S., D.S., J.B., K.P.L., Y.K., M.K.-S., D.N., and M.N.F. performed research; J.B., D.P.W., D.A., and E.R. contributed new reagents/analytic tools; K.S., D.S., J.B., D.P.W., K.P.L., Y.K., M.K.-S., D.N., D.A., S.N., J.N., T.M., E.R., N.Y., and M.N.F. analyzed data; and K.S., D.N., J.N., T.M., E.R., N.Y., and M.N.F. wrote the paper.

The authors declare no conflict of interest.

This article contains supporting information online at

§§To whom correspondence should be sent. E-mail: michiko{at}

© 2007 by The National Academy of Sciences of the USA

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