Determining the molecular mechanism of human embryo implantation is an extremely challenging task due to the limitation of materials and significant differences in this process among mammalian species. Trophinin has been identified as an apical cell adhesion molecule with potential involvement in human embryo implantation. We found that trophinin-mediated cell adhesion triggers signal transduction in human trophoblastic cells for proliferation and invasion, implicating in trophectoderm cell activation for placental formation. Prior to cell adhesion trophinin arrests ErbB4 by binding through bystin, which prevents ErbB4 from activation. Trophinin-mediated cell adhesion causes dissociation of bystin from trophinin, freeing ErbB4 from arrest and enabling tyrosine phosphorylation. Therefore trophinin functions as an adhesion molecule on the cell surface and as a molecular switch for trophoblast activation in the cytoplasm.