The membrane-spanning domain of CD98 heavy chain promotes alpha(v)beta3 integrin signals in human extravillous trophoblasts.
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, alpha(v)beta(3) integrin is expressed in a temporally and spatially specific manner, which prompted us to investigate the potential role of CD98hc in signal transduction of alpha(v)beta(3) integrin. Immunocytochemistry of extravillous trophoblast derived from human placenta revealed that CD98hc colocalized with alpha(v)beta(3) integrin and with alpha(v)beta(3)-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 alpha(v)beta(3) 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 alpha(v)beta(3)integrin, 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 alpha(v)beta(3) integrin-dependent signals.
Kabir-Salmani
Maryam
M
Department of Obstetrics and Gynecology, Kyorin University School of Medicine, shinkawa 6-20-2, Mitaka-shi, Tokyo 181-8611, Japan.
Fukuda
Michiko N
MN
Kanai-Azuma
Masami
M
Ahmed
Nesar
N
Shiokawa
Shigetatsu
S
Akimoto
Yoshihiro
Y
Sakai
Keiji
K
Nagamori
Seishi
S
Kanai
Yoshikatsu
Y
Sugihara
Kazuhiro
K
Iwashita
Mitsutoshi
M
D015374:Biosensing Techniques; D002448:Cell Adhesion / Q000502:physiology; D002460:Cell Line; D002465:Cell Movement / Q000502:physiology; D005260:Female; D005353:Fibronectins / Q000378:metabolism; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D027282:Fusion Regulatory Protein 1, Heavy Chain / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D008858:Microscopy, Phase-Contrast; D051419:Paxillin / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000494:pharmacology; D010766:Phosphorylation; D010920:Placenta / Q000378:metabolism*; D011247:Pregnancy; D015398:Signal Transduction; D014162:Transfection; D014327:Trophoblasts / Q000378:metabolism*; D016596:Vinculin / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
D005353:Fibronectins; D027282:Fusion Regulatory Protein 1, Heavy Chain; D039302:Integrin alphaVbeta3; D051419:Paxillin; D016596:Vinculin; D019869:Phosphatidylinositol 3-Kinases; D051416:Focal Adhesion Protein-Tyrosine Kinases; D020742:rhoA GTP-Binding Protein