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Copyright © 2000 by the American Society for Microbiology. All rights reserved.
Molecular and Cellular Biology, March 2000, p. 2098-2107, Vol. 20, No. 6 The Interaction between the Drosophila Secreted Protein Argos and the Epidermal Growth Factor Receptor Inhibits Dimerization of the Receptor and Binding of Secreted Spitz to the ReceptorDivision of Neuroanatomy, Department of Neuroscience, Biomedical Research Center, Osaka University Graduate School of Medicine, and Core Research for Evolutional Science and Technology (CREST) of Japan Science and Technology Corporation (JST),1 and Strategic Promotion System for Brain Science (SPSBS), Science and Technology Agency of Japan,2 Suita, Osaka 565-0871, Japan
Received 21 September 1999/Returned for modification 9 November 1999/Accepted 28 December 1999 Drosophila Argos (Aos), a secreted protein with an
epidermal growth factor (EGF)-like domain, has been shown to inhibit
the activation of the Drosophila EGF receptor (DER).
However, it has not been determined whether Aos binds directly to DER
or whether regulation of the DER activation occurs through some other
mechanism. Using DER-expressing cells (DER/S2) and a recombinant DER
extracellular domain-Fc fusion protein (DER-Fc), we have shown that Aos
binds directly to the extracellular domain of DER with its
carboxyl-terminal region, including the EGF-like domain. Furthermore,
Aos can block the binding of secreted Spitz (sSpi), a transforming
growth factor * Corresponding author. Mailing address: Division of Neuroanatomy (D12), Department of Neuroscience, Biomedical Research Center, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan. Phone: 81-6-6879-3581. Fax: 81-6-6879-3589. E-mail: okano{at}nana.med.osaka-u.ac.jp. Molecular and Cellular Biology, March 2000, p. 2098-2107, Vol. 20, No. 6 0270-7306/00/$04.00+0 Copyright © 2000, American Society for Microbiology. All rights reserved. THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
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-like ligand of DER, to the extracellular domain of
DER. We observed that sSpi stimulates the dimerization of both the
soluble DER extracellular domain (sDER) and the intact DER in the
DER/S2 cells and that Aos can block the sSpi-induced dimerization of
both sDER and intact DER. Moreover, we have shown that, by directly
interacting with DER, Aos and SpiAos (a chimeric protein that is
composed of the N-terminal region of Spi and the C-terminal region of
Aos) inhibit the dimerization and phosphorylation of DER that are
induced by DER's overexpression in the absence of sSpi. These results indicate that Aos exerts its inhibitory function through dual molecular
mechanisms: by blocking both the receptor dimerization and the binding
of activating ligand to the receptor. This is the first description of
this novel inhibitory mechanism for receptor tyrosine kinases.
Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882
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