Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Subscribe

Logo for

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
A STUDY WITH AN ABERRANT EPIDERMAL GROWTH FACTOR RECEPTOR (EGFRvIII/Delta EGFR) EXPRESSED IN CANCER CELLS*

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: bishayee@umdnj.edu.


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

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Characterization and Immunotherapeutic Implications for a Novel Antibody Targeting Interleukin (IL)-13 Receptor {alpha}2.
I. V. Balyasnikova, D. A. Wainwright, E. Solomaha, G. Lee, Y. Han, B. Thaci, and M. S. Lesniak (2012)
J. Biol. Chem. 287, 30215-30227
   Abstract »    Full Text »    PDF »
Quantitative Proteomic Profiling Identifies Protein Correlates to EGFR Kinase Inhibition.
K. Kani, V. M. Faca, L. D. Hughes, W. Zhang, Q. Fang, B. Shahbaba, R. Luethy, J. Erde, J. Schmidt, S. J. Pitteri, et al. (2012)
Mol. Cancer Ther. 11, 1071-1081
   Abstract »    Full Text »    PDF »
In Situ Analysis of Mutant EGFRs Prevalent in Glioblastoma Multiforme Reveals Aberrant Dimerization, Activation, and Differential Response to Anti-EGFR Targeted Therapy.
A. S. Gajadhar, E. Bogdanovic, D. M. Munoz, and A. Guha (2012)
Mol. Cancer Res. 10, 428-440
   Abstract »    Full Text »    PDF »
Asialoglycoprotein Receptor Promotes Cancer Metastasis by Activating the EGFR-ERK Pathway.
S. Ueno, M. Mojic, Y. Ohashi, N. Higashi, Y. Hayakawa, and T. Irimura (2011)
Cancer Res. 71, 6419-6427
   Abstract »    Full Text »    PDF »
The single kinin receptor signals to separate and independent physiological pathways in Malpighian tubules of the yellow fever mosquito.
S. A. Schepel, A. J. Fox, J. T. Miyauchi, T. Sou, J. D. Yang, K. Lau, A. W. Blum, L. K. Nicholson, F. Tiburcy, R. J. Nachman, et al. (2010)
Am J Physiol Regulatory Integrative Comp Physiol 299, R612-R622
   Abstract »    Full Text »    PDF »
The Constitutive Activity of Epidermal Growth Factor Receptor vIII Leads to Activation and Differential Trafficking of Wild-type Epidermal Growth Factor Receptor and erbB2.
R. Zeineldin, Y. Ning, and L. G. Hudson (2010)
Journal of Histochemistry & Cytochemistry 58, 529-541
   Abstract »    Full Text »    PDF »
GM3 synthase overexpression results in reduced cell motility and in caveolin-1 upregulation in human ovarian carcinoma cells.
A. Prinetti, M. Aureli, G. Illuzzi, S. Prioni, V. Nocco, F. Scandroglio, N. Gagliano, G. Tredici, V. Rodriguez-Menendez, V. Chigorno, et al. (2010)
Glycobiology 20, 62-77
   Abstract »    Full Text »    PDF »
Tyrosine Kinase Activity of Epidermal Growth Factor Receptor Is Regulated by GM3 Binding through Carbohydrate to Carbohydrate Interactions.
N. Kawashima, S.-J. Yoon, K. Itoh, and K.-i. Nakayama (2009)
J. Biol. Chem. 284, 6147-6155
   Abstract »    Full Text »    PDF »
Tetraspanin CD151 Regulates Glycosylation of {alpha}3{beta}1 Integrin.
G. Baldwin, V. Novitskaya, R. Sadej, E. Pochec, A. Litynska, C. Hartmann, J. Williams, L. Ashman, J. A. Eble, and F. Berditchevski (2008)
J. Biol. Chem. 283, 35445-35454
   Abstract »    Full Text »    PDF »
EGFR and erbB2 in malignant peripheral nerve sheath tumors and implications for targeted therapy.
N. Holtkamp, E. Malzer, J. Zietsch, A. F. Okuducu, J. Mucha, C. Mawrin, V.-F. Mautner, H.-U. Schildhaus, and A. von Deimling (2008)
Neuro Oncology 10, 946-957
   Abstract »    Full Text »    PDF »
N-Glycans in cancer progression.
K. S Lau and J. W Dennis (2008)
Glycobiology 18, 750-760
   Abstract »    Full Text »    PDF »
Inhibition of N-Linked Glycosylation Disrupts Receptor Tyrosine Kinase Signaling in Tumor Cells.
J. N. Contessa, M. S. Bhojani, H. H. Freeze, A. Rehemtulla, and T. S. Lawrence (2008)
Cancer Res. 68, 3803-3809
   Abstract »    Full Text »    PDF »
Gas6-Axl Receptor Signaling Is Regulated by Glucose in Vascular Smooth Muscle Cells.
M. E. Cavet, E. M. Smolock, O. H. Ozturk, C. World, J. Pang, A. Konishi, and B. C. Berk (2008)
Arterioscler Thromb Vasc Biol 28, 886-891
   Abstract »    Full Text »    PDF »
EGFRvIII escapes down-regulation due to impaired internalization and sorting to lysosomes.
M. V. Grandal, R. Zandi, M. W. Pedersen, B. M. Willumsen, B. van Deurs, and H. S. Poulsen (2007)
Carcinogenesis 28, 1408-1417
   Abstract »    Full Text »    PDF »
Functional consequences of alteration of N-linked glycosylation sites on the neurokinin 1 receptor.
M. F. Tansky, C. Pothoulakis, and S. E. Leeman (2007)
PNAS 104, 10691-10696
   Abstract »    Full Text »    PDF »
Epidermal growth factor receptor tyrosine kinase is modulated by GM3 interaction with N-linked GlcNAc termini of the receptor.
S.-J. Yoon, K.-i. Nakayama, T. Hikita, K. Handa, and S.-i. Hakomori (2006)
PNAS 103, 18987-18991
   Abstract »    Full Text »    PDF »
High predictive value of epidermal growth factor receptor phosphorylation but not of EGFRvIII mutation in resected stage I non-small cell lung cancer (NSCLC)..
B Sonnweber, M Dlaska, S Skvortsov, S Dirnhofer, T Schmid, and W Hilbe (2006)
J. Clin. Pathol. 59, 255-259
   Abstract »    Full Text »    PDF »
Hierarchical Regulation of CTLA-4 Dimer-Based Lattice Formation and Its Biological Relevance for T Cell Inactivation.
P. J. Darlington, M. G. Kirchhof, G. Criado, J. Sondhi, and J. Madrenas (2005)
J. Immunol. 175, 996-1004
   Abstract »    Full Text »    PDF »
Resistance to Tyrosine Kinase Inhibition by Mutant Epidermal Growth Factor Receptor Variant III Contributes to the Neoplastic Phenotype of Glioblastoma Multiforme.
C. A. Learn, T. L. Hartzell, C. J. Wikstrand, G. E. Archer, J. N. Rich, A. H. Friedman, H. S. Friedman, D. D. Bigner, and J. H. Sampson (2004)
Clin. Cancer Res. 10, 3216-3224
   Abstract »    Full Text »    PDF »
Tetraspanin CD82 regulates compartmentalisation and ligand-induced dimerization of EGFR.
E. Odintsova, J. Voortman, E. Gilbert, and F. Berditchevski (2003)
J. Cell Sci. 116, 4557-4566
   Abstract »    Full Text »    PDF »
E-Selectin Polymorphism Associated With Myocardial Infarction Causes Enhanced Leukocyte-Endothelial Interactions Under Flow Conditions.
M. Yoshida, Y. Takano, T. Sasaoka, T. Izumi, and A. Kimura (2003)
Arterioscler Thromb Vasc Biol 23, 783-788
   Abstract »    Full Text »    PDF »
MuSK Glycosylation Restrains MuSK Activation and Acetylcholine Receptor Clustering.
A. Watty and S. J. Burden (2002)
J. Biol. Chem. 277, 50457-50462
   Abstract »    Full Text »    PDF »
Second Cysteine-rich Region of Epidermal Growth Factor Receptor Contains Targeting Information for Caveolae/Rafts.
M. Yamabhai and R. G. W. Anderson (2002)
J. Biol. Chem. 277, 24843-24846
   Abstract »    Full Text »    PDF »
The glycosynapse.
S.-i. Hakomori (2002)
PNAS 99, 225-232
   Abstract »    Full Text »    PDF »
The glycosynapse.
S.-i. Hakomori (2002)
PNAS 99, 225-232
   Abstract »    Full Text »    PDF »

To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882