QUICK SEARCH:   [advanced] Author: Keyword(s):
Home     Help     Feedback     Subscriptions     Archive     Search     Table of Contents

First published online 9 September 2008
doi: 10.1242/jcs.033399

This Article Figures Only Full Text Full Text (PDF) Supplementary Material OA All Versions of this Article: jcs.033399v1 121/19/3207    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Tao, R.-H. Articles by Maruyama, I. N. PubMed PubMed Citation Articles by Tao, R.-H. Articles by Maruyama, I. N.

All EGF(ErbB) receptors have preformed homo- and heterodimeric structures in living cells

Information Processing Biology Unit, Okinawa Institute of Science and Technology, 12-2 Suzaki, Uruma, Okinawa 904-2234, Japan

^* Author for correspondence (e-mail: ichi{at}oist.jp)

Accepted 17 July 2008

The epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases, also known as ErbB or HER, plays crucial roles in the development of multicellular organisms. Mutations and over-expression of the ErbB receptors have been implicated in a variety of human cancers. It is widely thought that the ErbB receptors are located in the plasma membrane, and that ligand binding to the monomeric form of the receptors induces its dimeric form for activation. However, it still remains controversial whether prior to ligand binding the receptors exist as monomers or dimers on the cell surface. Using bimolecular fluorescence complementation (BiFC) assays in the present study, we demonstrate that in the absence of bound ligand, all the ErbB family members have preformed, yet inactive, homo- and heterodimers on the cell surface, except for ErbB3 homodimers and heterodimers with cleavable ErbB4, which exist primarily in the nucleus. BiFC assays of the dimerization have also suggested that the ligand-independent dimerization of the ErbB receptors occurs in the endoplasmic reticulum (ER) before newly synthesized receptor molecules reach the cell surface. Based on BiFC and mammalian two-hybrid assays, it is apparent that the intracellular domains of the receptors are responsible for the spontaneous dimer formation. These provide new insights into an understanding of transmembrane signal transduction mediated by the ErbB family members, and are relevant to the development of anti-cancer drugs.

Key words: Cancer, Dimerization, Epidermal growth factor receptor, ErbB, Molecular mechanism, Transmembrane signal transduction