The membrane-spanning domain of CD98 heavy chain promotes αvβ3 integrin signals in human extravillous trophoblasts

Maryam Kabir-Salmani, Michiko N. Fukuda, Masami Kanai-Azuma, Nesar Ahmed, Shigetatsu Shiokawa, Yoshihiro Akimoto, Keiji Sakai, Seishi Nagamori, Yoshikatsu Kanai, Kazuhiro Sugihara, Mitsutoshi Iwashita

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23 Citations (Scopus)


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, αvβ3 integrin is expressed in a temporally and spatially specific manner, which prompted us to investigate the potential role of CD98hc in signal transduction of αvβ3 integrin. Immunocytochemistry of extravillous trophoblast derived from human placenta revealed that CD98hc colocalized with αvβ3 integrin and with αvβ3-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 αvβ3 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 αvβ3integrin, 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 αvβ 3 integrin-dependent signals.

Original languageEnglish
Pages (from-to)707-715
Number of pages9
JournalMolecular Endocrinology
Issue number3
Publication statusPublished - 03-2008
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Endocrinology


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