title: Trophoblast cell activation by trophinin ligation is implicated in human embryo implantation.
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.
authors.affiliation: Cancer Research Center and Inflammation and Infectious Disease Center, Burnham Institute for Medical Research, 10901 North Torrey Pines Road, La Jolla, CA 92037.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Sugihara
authors.forename: Daijiro
authors.initials: D
authors.lastname: Sugiyama
authors.forename: James
authors.initials: J
authors.lastname: Byrne
authors.forename: Don P
authors.initials: DP
authors.lastname: Wolf
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Lowitz
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Kobayashi
authors.forename: Maryam
authors.initials: M
authors.lastname: Kabir-Salmani
authors.forename: Daita
authors.initials: D
authors.lastname: Nadano
authors.forename: Daisuke
authors.initials: D
authors.lastname: Aoki
authors.forename: Shiro
authors.initials: S
authors.lastname: Nozawa
authors.forename: Jun
authors.initials: J
authors.lastname: Nakayama
authors.forename: Tomas
authors.initials: T
authors.lastname: Mustelin
authors.forename: Erkki
authors.initials: E
authors.lastname: Ruoslahti
authors.forename: Naoto
authors.initials: N
authors.lastname: Yamaguchi
authors.forename: Michiko N
authors.initials: MN
authors.lastname: Fukuda
mesh_terms: D000199:Actins / Q000737:chemistry; D000595:Amino Acid Sequence; D000818:Animals; D015815:Cell Adhesion Molecules / Q000737:chemistry / Q000502:physiology*; D010064:Embryo Implantation; D066246:ErbB Receptors / Q000737:chemistry; D005260:Female; D006801:Humans; D008253:Macaca mulatta; D008297:Male; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011247:Pregnancy; D011485:Protein Binding; D066247:Receptor, ErbB-4; D014327:Trophoblasts / Q000378:metabolism*
chemical_list: D000199:Actins; D015815:Cell Adhesion Molecules; C093649:TRO protein, human; C587689:ERBB4 protein, human; D066246:ErbB Receptors; D066247:Receptor, ErbB-4