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The Membrane-Spanning Domain of CD98 Heavy Chain Promotes _vβ₃ Integrin Signals in Human Extravillous Trophoblasts

Departments of Obstetrics and Gynecology (M.K-S., S.S., Ke.S., Ka.S., M.I.), Anatomy, Pharmacology and Toxicology (N.A., Y.K.), General Medicine (S.N.), Kyorin University School of Medicine, Tokyo 181-8611, Japan; Molecular and Cellular Research Center (M.K-A.), Faculty of Medicine, Shahid Beheshti Medical University, and Department of Medical Genetics, National Institute of Genetic Engineering and Biotechnology, Tehran 19835-177, Iran; and Tumor Microenvironment Program (M.N.F.), Cancer Research Center, Burnham Institute for Medical Research, La Jolla, California 92037

Address all correspondence and requests for reprints to: Michiko N. Fukuda, Burnham Institute for Medical Research, 10901 North Torrey Pines Road, La Jolla, California 92037. E-mail: michiko{at}burnham.org; and Mitsutoshi Iwashita, Department of Obstetrics and Gynecology, Kyorin University School of Medicine, shinkawa 6-20-2, Mitaka-shi, Tokyo 181-8611, Japan. E-mail: iwashita{at}kyorin-u.ac.jp.

CD98 heavy chain (CD98hc) is expressed highly in developing human placental trophoblast. CD98hc is an amino acid transporter and is thought to function in cell fusion, adhesion, and invasion by interacting with integrins. In invasive extravillous trophoblast, _vβ₃ integrin is expressed in a temporally and spatially specific manner, which prompted us to investigate the potential role of CD98hc in signal transduction of _vβ₃ integrin. Immunocytochemistry of extravillous trophoblast derived from human placenta revealed that CD98hc colocalized with _vβ₃ integrin and with _vβ₃-associated cytoplasmic proteins including paxillin, vinculin, and focal adhesion kinase. Coimmunoprecipitation of CD98hc and its mutants revealed that the transmembrane domain of CD98hc is necessary for the association of CD98hc with _vβ₃ integrin. When CD98hc negative liver cells (FLC4) were stably transfected with CD98hc and the extracellular domain of CD98hc was cross-linked by anti-CD98 antibody, FLC4 cells binding affinity to fibronectin and cell motility increased. The anti-CD98 antibody cross-linking promoted actin stress fiber formation and activation of signal transduction downstream of RhoA GTPase, and elevated the phosphorylation of focal adhesion kinase, paxillin, and protein kinase B. Pretreatment of transfected FLC4 cells with specific inhibitors for _vβ₃integrin, phosphatidylinositol 3-kinase, and RhoA diminished these effects caused by anti-CD98 antibody cross-linking. These results suggest that notoriously invasive activity of extravillous trophoblast is mediated by CD98hc, which promotes _vβ₃ integrin-dependent signals.

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