title: Bikunin down-regulates heterodimerization between CD44 and growth factor receptors and subsequently suppresses agonist-mediated signaling.
abstract: We provided evidence previously that bikunin, a Kunitz-type protease inhibitor, can disrupt dimerization of CD44 proteins, which may result in suppression of receptor-mediated MAP kinase signaling. However, to what extent dimerization may alter ligand-induced signaling has not been documented. Given the recent recognition that some growth factor receptors can form heterodimers with CD44, the present study was undertaken to determine whether the CD44 and growth factor receptors (e.g., EGFR, FGFR, HGFR, VEGFR, TGF-betaRI, or TGF-betaRII) can form heterodimers in cancer cells and, if so, to investigate the potential functional consequences of such heterodimerization. We also examined whether bikunin can abrogate these heterodimerizations and inhibit CD44/growth factor-dependent signaling. Here, we show direct evidence for heterodimerization of CD44-FGFR and CD44-TGF-betaRI in human chondrosarcoma HCS-2/8 cells, CD44-EGFR complex in human glioma U87MG cells, and CD44-TGF-betaRI heterodimer in human ovarian cancer HRA cells. Coupling of CD44 and growth factor receptor may be selective, depending on a cell type. Bikunin does not alter the ligand binding, whereas functionally reduces heterodimerization between CD44 and growth factor receptors. The disruption of heterodimerization substantially reduces receptor-induced tyrosine phosphorylation and ERK1/2 activation. Taken together, our data suggest that bikunin-mediated suppression of heterodimerization between CD44 and growth factors may inhibit the agonist-promoted activation of the signaling pathway.
authors.affiliation: NetForce Co. Ltd., Taiko 3-1-18, Nakamura, Nagoya, Aichi 453-0801, Japan.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Wakahara
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kobayashi
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Yagyu
authors.forename: Hidenori
authors.initials: H
authors.lastname: Matsuzaki
authors.forename: Toshiharu
authors.initials: T
authors.lastname: Kondo
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Kurita
authors.forename: Hideo
authors.initials: H
authors.lastname: Sekino
authors.forename: Kiyokazu
authors.initials: K
authors.lastname: Inagaki
authors.forename: Mika
authors.initials: M
authors.lastname: Suzuki
authors.forename: Naohiro
authors.initials: N
authors.lastname: Kanayama
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Terao
mesh_terms: D045744:Cell Line, Tumor; D019281:Dimerization; D015536:Down-Regulation / Q000187:drug effects*; D004789:Enzyme Activation; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism*; D047468:Immunoprecipitation; D008562:Membrane Glycoproteins / Q000494:pharmacology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism*; D015398:Signal Transduction; D014360:Trypsin Inhibitor, Kunitz Soybean / Q000494:pharmacology*
chemical_list: D018960:Hyaluronan Receptors; D008562:Membrane Glycoproteins; D018125:Receptors, Transforming Growth Factor beta; C109148:SPINT2 protein, human; D014360:Trypsin Inhibitor, Kunitz Soybean; D020928:Mitogen-Activated Protein Kinases