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Mol. Cell. Biol. 20 (6): 2098-2107

Copyright © 2000 by the American Society for Microbiology. All rights reserved.

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.

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 Receptor

Ming-hao Jin,1 Kazunobu Sawamoto,1,2 Mikiko Ito,1 and Hideyuki Okano1,*

Division 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 alpha -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.


* 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.

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