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Molecular and Cellular Biology, September 1998, p. 5371-5379, Vol. 18, No. 9
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Activation of Neu (ErbB-2) Mediated by Disulfide Bond-Induced Dimerization Reveals a Receptor Tyrosine Kinase Dimer Interface

Christine L. Burkedagger and David F. Stern*

Department of Pathology, Yale University, New Haven, Connecticut 06520-8023

Received 4 September 1997/Returned for modification 24 October 1997/Accepted 3 June 1998

Receptor dimerization is a crucial intermediate step in activation of signaling by receptor tyrosine kinases (RTKs). However, dimerization of the RTK Neu (also designated ErbB-2, HER-2, and p185neu), while necessary, is not sufficient for signaling. Earlier work in our laboratory had shown that introduction of an ectopic cysteine into the Neu juxtamembrane domain induces Neu dimerization but not signaling. Since Neu signaling does require dimerization, we hypothesized that there are additional constraints that govern signaling ability. With the importance of the interreceptor cross-phosphorylation reaction, a likely constraint was the relative geometry of receptors within the dimer. We have tested this possibility by constructing a consecutive series of cysteine substitutions in the Neu juxtamembrane domain in order to force dimerization along a series of interreceptor faces. Within the group that dimerized constitutively, a subset had transforming activity. The substitutions in this subset all mapped to the same face of a predicted alpha helix, the most likely conformation for the intramembrane domain. Furthermore, this face of interaction aligns with the projected Neu* V664E substitution and with a predicted amphipathic interface in the Neu juxtamembrane domain. We propose that these results identify an RTK dimer interface and that dimerization of this RTK induces an extended contact between juxtamembrane and intramembrane alpha helices.

* Corresponding author. Mailing address: Dept. of Pathology, Yale University, 310 Cedar St., Room BML 342, New Haven, CT 06520-8023. Phone: (203) 785-4832. Fax: (203) 785-7467. E-mail: Stern{at}biomed.med.yale.edu.

dagger Present address: Dept. of Lab Medicine, University of California---San Francisco, San Francisco, CA 94143-0100.

Molecular and Cellular Biology, September 1998, p. 5371-5379, Vol. 18, No. 9
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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