This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Burke, C. L.
Right arrow Articles by Stern, D. F.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Burke, C. L.
Right arrow Articles by Stern, D. F.

 Previous Article  |  Next Article 

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.


This article has been cited by other articles:

  • Finger, C., Escher, C., Schneider, D. (2009). The Single Transmembrane Domains of Human Receptor Tyrosine Kinases Encode Self-Interactions. Sci Signal 2: ra56-ra56 [Abstract] [Full Text]  
  • Vilar, M., Charalampopoulos, I., Kenchappa, R. S., Reversi, A., Klos-Applequist, J. M., Karaca, E., Simi, A., Spuch, C., Choi, S., Friedman, W. J., Ericson, J., Schiavo, G., Carter, B. D., Ibanez, C. F. (2009). Ligand-independent signaling by disulfide-crosslinked dimers of the p75 neurotrophin receptor. J. Cell Sci. 122: 3351-3357 [Abstract] [Full Text]  
  • Kubatzky, K. F., Liu, W., Goldgraben, K., Simmerling, C., Smith, S. O., Constantinescu, S. N. (2005). Structural Requirements of the Extracellular to Transmembrane Domain Junction for Erythropoietin Receptor Function. J. Biol. Chem. 280: 14844-14854 [Abstract] [Full Text]  
  • Lynch, M., Fitzgerald, C., Johnston, K. A., Wang, S., Schmidt, E. V. (2004). Activated eIF4E-binding Protein Slows G1 Progression and Blocks Transformation by c-myc without Inhibiting Cell Growth. J. Biol. Chem. 279: 3327-3339 [Abstract] [Full Text]  
  • Renard, V., Sonderbye, L., Ebbehoj, K., Rasmussen, P. B., Gregorius, K., Gottschalk, T., Mouritsen, S., Gautam, A., Leach, D. R. (2003). HER-2 DNA and Protein Vaccines Containing Potent Th Cell Epitopes Induce Distinct Protective and Therapeutic Antitumor Responses in HER-2 Transgenic Mice. J. Immunol. 171: 1588-1595 [Abstract] [Full Text]  
  • Irusta, P. M., Luo, Y., Bakht, O., Lai, C.-C., Smith, S. O., DiMaio, D. (2002). Definition of an Inhibitory Juxtamembrane WW-like Domain in the Platelet-derived Growth Factor beta Receptor. J. Biol. Chem. 277: 38627-38634 [Abstract] [Full Text]  
  • Gilliland, D. G., Griffin, J. D. (2002). The roles of FLT3 in hematopoiesis and leukemia. Blood 100: 1532-1542 [Abstract] [Full Text]  
  • Penuel, E., Akita, R. W., Sliwkowski, M. X. (2002). Identification of a Region within the ErbB2/HER2 Intracellular Domain That Is Necessary for Ligand-independent Association. J. Biol. Chem. 277: 28468-28473 [Abstract] [Full Text]  
  • Yu, X., Sharma, K. D., Takahashi, T., Iwamoto, R., Mekada, E. (2002). Ligand-independent Dimer Formation of Epidermal Growth Factor Receptor (EGFR) Is a Step Separable from Ligand-induced EGFR Signaling. Mol. Biol. Cell 13: 2547-2557 [Abstract] [Full Text]  
  • Penington, D. J., Bryant, I., Riese, D. J. II (2002). Constitutively Active ErbB4 and ErbB2 Mutants Exhibit Distinct Biological Activities. Cell Growth Differ. 13: 247-256 [Abstract] [Full Text]  
  • Nahta, R., Iglehart, J. D., Kempkes, B., Schmidt, E. V. (2002). Rate-limiting Effects of Cyclin D1 in Transformation by ErbB2 Predicts Synergy between Herceptin and Flavopiridol. Cancer Res. 62: 2267-2271 [Abstract] [Full Text]  
  • Mendrola, J. M., Berger, M. B., King, M. C., Lemmon, M. A. (2002). The Single Transmembrane Domains of ErbB Receptors Self-associate in Cell Membranes. J. Biol. Chem. 277: 4704-4712 [Abstract] [Full Text]  
  • Yip, Y. L., Smith, G., Koch, J., Dubel, S., Ward, R. L. (2001). Identification of Epitope Regions Recognized by Tumor Inhibitory and Stimulatory Anti-ErbB-2 Monoclonal Antibodies: Implications for Vaccine Design. J. Immunol. 166: 5271-5278 [Abstract] [Full Text]  
  • Fiorentino, L., Pertica, C., Fiorini, M., Talora, C., Crescenzi, M., Castellani, L., Alemà, S., Benedetti, P., Segatto, O. (2000). Inhibition of ErbB-2 Mitogenic and Transforming Activity by RALT, a Mitogen-Induced Signal Transducer Which Binds to the ErbB-2 Kinase Domain. Mol. Cell. Biol. 20: 7735-7750 [Abstract] [Full Text]  
  • Bell, C. A., Tynan, J. A., Hart, K. C., Meyer, A. N., Robertson, S. C., Donoghue, D. J. (2000). Rotational Coupling of the Transmembrane and Kinase Domains of the Neu Receptor Tyrosine Kinase. Mol. Biol. Cell 11: 3589-3599 [Abstract] [Full Text]  
  • Maliartchouk, S., Debeir, T., Beglova, N., Cuello, A. C., Gehring, K., Saragovi, H. U. (2000). Genuine Monovalent Ligands of TrkA Nerve Growth Factor Receptors Reveal a Novel Pharmacological Mechanism of Action. J. Biol. Chem. 275: 9946-9956 [Abstract] [Full Text]  
  • Lai, C.-C., Henningson, C., DiMaio, D. (2000). Bovine Papillomavirus E5 Protein Induces the Formation of Signal Transduction Complexes Containing Dimeric Activated Platelet-derived Growth Factor beta Receptor and Associated Signaling Proteins. J. Biol. Chem. 275: 9832-9840 [Abstract] [Full Text]  
  • Muthuswamy, S. K., Gilman, M., Brugge, J. S. (1999). Controlled Dimerization of ErbB Receptors Provides Evidence for Differential Signaling by Homo- and Heterodimers. Mol. Cell. Biol. 19: 6845-6857 [Abstract] [Full Text]  
  • Tessitore, A., Sinisi, A. A., Pasquali, D., Cardone, M., Vitale, D., Bellastella, A., Colantuoni, V. (1999). A Novel Case of Multiple Endocrine Neoplasia Type 2A Associated with Two de Novo Mutations of the RETProtooncogene. J. Clin. Endocrinol. Metab. 84: 3522-3527 [Abstract] [Full Text]  
  • Sweeney, C., Lai, C., Riese, D. J. II, Diamonti, A. J., Cantley, L. C., Carraway, K. L. III (2000). Ligand Discrimination in Signaling through an ErbB4 Receptor Homodimer. J. Biol. Chem. 275: 19803-19807 [Abstract] [Full Text]  
  • Born, T. L., Smith, D. E., Garka, K. E., Renshaw, B. R., Bertles, J. S., Sims, J. E. (2000). Identification and Characterization of Two Members of a Novel Class of the Interleukin-1 Receptor (IL-1R) Family. DELINEATION OF A NEW CLASS OF IL-1R-RELATED PROTEINS BASED ON SIGNALING. J. Biol. Chem. 275: 29946-29954 [Abstract] [Full Text]  
  • Ray, K., Hauschild, B. C. (2000). Cys-140 Is Critical for Metabotropic Glutamate Receptor-1 Dimerization. J. Biol. Chem. 275: 34245-34251 [Abstract] [Full Text]  
  • Gomez, A., Wellbrock, C., Gutbrod, H., Dimitrijevic, N., Schartl, M. (2001). Ligand-independent Dimerization and Activation of the Oncogenic Xmrk Receptor by Two Mutations in the Extracellular Domain. J. Biol. Chem. 276: 3333-3340 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»