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J. Biol. Chem. 276 (7): 5375-5383

© 2001 by The American Society for Biochemistry and Molecular Biology, Inc.

Glycosylation-induced Conformational Modification Positively Regulates Receptor-Receptor Association

Helen Fernandes, Stanley Cohen, and Subal BishayeeDagger

From the Department of Pathology and Laboratory Medicine, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark, New Jersey 07103

The epidermal growth factor receptor (EGFR) is a multisited and multifunctional transmembrane glycoprotein with intrinsic tyrosine kinase activity. Upon ligand binding, the monomeric receptor undergoes dimerization resulting in kinase activation. The consequences of kinase stimulation are the phosphorylation of its own tyrosine residues (autophosphorylation) followed by association with and activation of signal transducers. Deregulation of signaling resulting from aberrant expression of the EGFR has been implicated in a number of neoplasms including breast, brain, and skin tumors. A mutant epidermal growth factor (EGF) receptor missing 267 amino acids from the exoplasmic domain is common in human glioblastomas. The truncated receptor (EGFRvIII/Delta EGFR) lacks EGF binding activity; however, the kinase is constitutively active, and cells expressing the receptor are tumorigenic. Our studies revealed that the high kinase activity of the Delta EGFR is due to self-dimerization, and contrary to earlier reports, the kinase activity per molecule of the dimeric Delta EGFR is comparable to that of the EGF-stimulated wild-type receptor. Furthermore, the phosphorylation patterns of both receptors are similar as determined by interaction with a conformation-specific antibody and by phosphopeptide analysis. This eliminates the possibility that the defective down-regulation of the Delta EGFR is due to its altered phosphorylation pattern as has been suggested previously. Interestingly, the receptor-receptor self-association is highly dependent on a conformation induced by N-linked glycosylation. We have identified four potential sites that might participate in self-dimerization; these sites are located in a domain that plays an important role in EGFR functioning.

* This work was supported in part by a grant from the Foundation of the University of Medicine and Dentistry of New Jersey (to S. B.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger To whom correspondence should be addressed: Medical Science Bldg., Rm. C-567, Dept. of Pathology and Laboratory Medicine, UMDNJ-New Jersey Medical School, 185 S. Orange Ave., Newark, NJ 07103-2714. Tel.: 973-972-2623; Fax: 973-972-5909; E-mail:

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.

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